bims-smotar Biomed News
on Small molecule targeting of RNA
Issue of 2023–02–19
99 papers selected by
Rabia T. Khan, Serna Bio
  1. Pseudoknots in RNA Structure Prediction.
  2. The function of long non-coding RNA in non-alcoholic fatty liver disease.
  3. Long non-coding RNA signature in colorectal cancer: research progression and clinical application.
  4. Long Non-coding RNAs: Pivotal Epigenetic Regulators in Diabetic Retinopathy.
  5. tRNA-derived small RNAs in plant response to biotic and abiotic stresses.
  6. Small RNAs in Cnidaria: A review.
  7. Structural Analysis of MALAT1 long non-coding RNA in cells and in evolution.
  8. Targeting Non-Coding RNA for CNS Injuries: Regulation of Blood-Brain Barrier Functions.
  9. TUG1 aggravates intracerebral hemorrhage injury by inhibiting angiogenesis in an miR-26a-dependent manner.
  10. SHAMAN: A mixed solvent molecular dynamics protocol to identify small-molecules binding sites on RNA structural ensembles.
  11. RNA structure controls assembly of multi-layered paraspeckles.
  12. FinO/ProQ-family proteins: an evolutionary perspective.
  13. RNA modification in mRNA cancer vaccines.
  14. RNA Dysmetabolism and Repeat-Associated Non-AUG Translation in Frontotemporal Lobar Degeneration/Amyotrophic Lateral Sclerosis due to C9orf72 Hexanucleotide Repeat Expansion.
  15. Transfer RNA-derived small RNAs in tumor microenvironment.
  16. RNA Secondary Structures with Given Motif Specification: Combinatorics and Algorithms.
  17. Expression profiles of lncRNAs and their possible regulatory role in monocrotaline-induced HSOS in rats.
  18. Long non-coding RNA DLGAP1-AS1 modulates the development of non-small-cell lung cancer via the microRNA-193a-5p/DTL axis.
  19. Differential nuclear import regulates nuclear RNA inheritance following mitosis.
  20. Integrative analysis of the expression profiles of whole coding and non-coding RNA transcriptomes and construction of the competing endogenous RNA networks for chronic obstructive pulmonary disease.
  21. Understanding cooperativity effects in RNA structure probing experiments.
  22. The lncRNA XIST/miR-150-5p/c-Fos axis regulates sepsis-induced myocardial injury via TXNIP-modulated pyroptosis.
  23. The covalent nucleotide modifications within plant mRNAs: What we know, how we find them, and what should be done in the future.
  24. Targeting epigenetic regulators to overcome drug resistance in cancers.
  25. Long non-coding RNA PSMG3 Antisense RNA 1 is correlated with oral squamous cell carcinoma and regulates cancer cell proliferation by targeting premature microRNA-141.
  26. LncRNA SLCO4A1-AS1 modulates colon cancer stem cell properties by binding to miR-150-3p and positively regulating SLCO4A1.
  27. RNA structure directs the targeting specificity of Cas13d.
  28. Transfer RNA halves are found as nicked tRNAs in cells: evidence that nicked tRNAs regulate expression of an RNA repair operon.
  29. Long non-coding RNA MYU promotes ovarian cancer cell proliferation by sponging miR-6827-5p and upregulating HMGA1.
  30. The long non-coding RNA THBS1-AS1 promotes cardiac fibroblast activation in cardiac fibrosis by regulating TGFBR1.
  31. Diverse Functions of MiR-425 in Human Cancer.
  32. Modeling of RNA-only structures.
  33. The structural features of the ligand-free moaA riboswitch and its ion-dependent folding.
  34. vsiRNA18 derived from tobacco curly shoot virus can regulate virus infection in Nicotiana benthamiana.
  35. Characterization of structures and molecular interactions of RNA and lipid carriers using atomic force microscopy.
  36. LncRNA UCC promotes epithelial-mesenchymal transition via the miR-143-3p/SOX5 axis in non-small-cell lung cancer.
  37. Neuronal stress granules as dynamic microcompartments: current concepts and open questions.
  38. Application value of circulating LncRNA in diagnosis, treatment, and prognosis of breast cancer.
  39. Long non-coding RNA BC002811 Promotes Gastric Cancer Metastasis by Regulating SOX2 Binding to the PTEN Promoter.
  40. MBNL1-AS1 Promotes Hypoxia-Induced Myocardial Infarction via the miR-132-3p/RAB14/CAMTA1 Axis.
  41. The RNA-RNA interactome between a phage and its satellite virus reveals a small RNA that differentially regulates gene expression across both genomes.
  42. Regulation of mRNA stability contributes to the function of innate lymphoid cells in various diseases.
  43. MiR-181a-5p inhibits uveal melanoma development by targeting GNAQ and AKT3.
  44. Probing the role of RNA in prion protein and prion fibril recognition.
  45. Long non-coding RNA CCL14-AS suppresses invasiveness and lymph node metastasis of colorectal cancer cells by regulating MEP1A.
  46. Regulation of LRRK2 dynamics and conformation states by small molecules.
  47. In vivo disruption of nuclear HSATII RNA biomolecular condensates.
  48. Ataxin-2 polyglutamine expansions aberrantly sequester TDP-43, drive ribonucleoprotein condensate transport dysfunction and suppress local translation.
  49. Feeding Asian honeybee queens with European honeybee royal jelly alters body color and expression of related coding and non-coding RNAs.
  50. D-RNA selects L-amino acids in a newly characterized aminoacyl-RNA loop ligation.
  51. Extensive Recoding of the Neural Proteome in Cephalopods by RNA Editing.
  52. Emerging roles of tRNA-derived fragments in cancer.
  53. Novel Perspectives for the Diagnosis and Treatment of Gynecological Cancers using Dysregulation of PIWI Protein and PiRNAs as Biomarkers.
  54. Structural basis for inactivation of PRC2 by G-quadruplex RNA.
  55. Knockdown of lncRNA SNHG16 attenuates myocardial ischemia‑reoxygenation injury via targeting miR‑183/FOXO1 axis.
  56. LncRNA SNHG15 relieves hyperglycemia-induced endothelial dysfunction via increased ubiquitination of thioredoxin-interacting protein.
  57. Quercetin selectively reduces expanded repeat RNA levels in models of myotonic dystrophy.
  58. LncRNA SNHG5 upregulation induced by YY1 contributes to angiogenesis via miR-26b/CTGF/VEGFA axis in acute myelogenous leukemia.
  59. Promiscuous splicing-derived hairpins are dominant substrates of tailing-mediated defense of miRNA biogenesis in mammals.
  60. The Effects of RNA.DNA-DNA Triple Helices on Nucleosome Structures and Dynamics.
  61. RNA Management During T7 Infection.
  62. Structure and dynamics of RNA in biomolecular condensate.
  63. Quality control ensures fidelity in ribosome assembly and cellular health.
  64. A comprehensive survey of C. elegans argonaute proteins reveals organism-wide gene regulatory networks and functions.
  65. Chemoproteomic discovery of a human RNA ligase.
  66. Corrigendum: Role of non-coding RNA in the pathophysiology and treatment of intrauterine adhesion.
  67. Dynamical control enables the formation of demixed biomolecular condensates.
  68. RNA excited states by NMR and their impact on function.
  69. The regulatory function of lncRNA and constructed network in epilepsy.
  70. LncRNA PCAT6 promotes proliferation, migration, invasion, and epithelial-mesenchymal transition of lung adenocarcinoma cell by targeting miR-545-3p.
  71. Role of cytoskeleton-related proteins in the acrosome reaction of Eriocheir sinensis spermatozoa.
  72. PerturbSci-Kinetics : Dissecting key regulators of transcriptome kinetics through scalable single-cell RNA profiling of pooled CRISPR screens.
  73. Genome-wide characterization of the PP2C gene family in peanut (Arachis hypogaea L.) and the identification of candidate genes involved in salinity-stress response.
  74. PrePCI: A structure- and chemical similarity-informed database of predicted protein compound interactions.
  75. Rationally Designed Synthetic Vectors for Therapeutic Nucleic Acid Delivery against Human Cytomegalovirus Infection.
  76. Inverse-folding design of yeast telomerase RNA increases activity in vitro.
  77. Evaluation of long noncoding RNA (LncRNA) in pathogenesis of HELLP syndrome: diagnostic and future approach.
  78. Regulatory roles of non-coding RNAs and m6A modification in trophoblast functions and the occurrence of its related adverse pregnancy outcomes.
  79. Environmentally Induced Sperm RNAs Transmit Cancer Susceptibility to Offspring in a Mouse Model.
  80. Long non-coding RNA telomerase RNA elements improve glucocorticoid-induced osteoporosis by EZH2 to regulate DKK1.
  81. Towards a unified pipeline for tissue-scale localization and identification of individual RNA molecules.
  82. Long Noncoding RNA LINC01503 Silencing Suppresses KLK4 Expression to Impede Pancreatic Cancer Development as miR-1321 Sponge.
  83. Copy Number Variation and Osteoporosis.
  84. Direct observation of RNA structure and dynamics in repeat-RNA assemblies using single molecule fluorescence microscopy.
  85. A novel pyroptosis gene expression-based risk score for survival in gastric cancer.
  86. MS0621, a novel small-molecule modulator of Ewing sarcoma chromatin accessibility, interacts with an RNA-associated macromolecular complex and influences RNA splicing.
  87. RNA structure controls composition and network dynamics of condensates.
  88. Polymer-based mRNA delivery strategies for advanced therapies.
  89. A review on the role of LINC00173 in human cancers.
  90. Construction of PARPi Resistance-related Competing Endogenous RNA Network.
  91. Gene expression differences consistent with water loss reduction underlie desiccation tolerance of natural Drosophila populations.
  92. Multivalent interactions between RNA and RNA binding proteins drive differential intra-speckle positioning of RNA transcripts.
  93. Leukemia/lymphoma-related factor (LRF) or osteoclast zinc finger protein (OCZF) overexpression promotes osteoclast survival by increasing Bcl-xl mRNA: A novel regulatory mechanism mediated by the RNA binding protein SAM68.
  94. The role of RNA condensation in reducing gene expression noise.
  95. Emerging landscape of circFNDC3B and its role in human malignancies.
  96. RNA secondary structure modulates the co-translational association of hERG1a and 1b mRNAs.
  97. Emerging role of non-coding RNAs in resistance to platinum-based anti-cancer agents in lung cancer.
  98. MicroRNA-432-5p regulates sprouting and intussusceptive angiogenesis in osteosarcoma microenvironment by targeting PDGFB.
  99. Long Non-coding RNA XIST Impedes LPS-induced AC16 Cell Inflammation and Apoptosis through Down-regulating miR-370-3p and Regulating PI3K/AKT/mTOR Pathways.
  1. Curr Protoc. 2023 Feb;3(2): e661
    Pseudoknots in RNA Structure Prediction.
    Andrew Hollar, Hunter Bursey, Hosna Jabbari.
      RNA molecules play active roles in the cell and are important for numerous applications in biotechnology and medicine. The function of an RNA molecule stems from its structure. RNA structure determination is time consuming, challenging, and expensive using experimental methods. Thus, much research has been directed at RNA structure prediction through computational means. Many of these methods focus primarily on the secondary structure of the molecule, ignoring the possibility of pseudoknotted structures. However, pseudoknots are known to play functional roles in many RNA molecules or in their method of interaction with other molecules. Improving the accuracy and efficiency of computational methods that predict pseudoknots is an ongoing challenge for single RNA molecules, RNA-RNA interactions, and RNA-protein interactions. To improve the accuracy of prediction, many methods focus on specific applications while restricting the length and the class of the pseudoknotted structures they can identify. In recent years, computational methods for structure prediction have begun to catch up with the impressive developments seen in biotechnology. Here, we provide a non-comprehensive overview of available pseudoknot prediction methods and their best-use cases. © 2023 Wiley Periodicals LLC.
    Keywords:  RNA interaction prediction; RNA secondary structure prediction; RNA-RNA; RNA-protein; isolated RNA; pseudoknot
    DOI:  https://doi.org/10.1002/cpz1.661
  2. Clin Res Hepatol Gastroenterol. 2023 Feb 11. pii: S2210-7401(23)00020-7. [Epub ahead of print] 102095
    The function of long non-coding RNA in non-alcoholic fatty liver disease.
    Lianrui Cao, Na Qu, Xin Wang, Lijiang Chen, Mingxia Liu.
      Non-alcoholic fatty liver disease is a disease that is currently prevalent in the world, increasingly becoming the mainstay of liver diseases. And its prevalence is rapidly increasing, but its pathogenesis is not entirely understood. Long non-coding RNAs have increasingly gained attention as science has progressed in recent years. Studies have shown that long non-coding RNAs are involved in a variety of biological processes in vivo, such as proliferation, differentiation, and apoptosis, and can affect disease by regulating gene expression. This review explores the biological processes involving long non-coding RNAs, including lipid metabolism, glucose metabolism, liver fibrosis, and apoptosis. In addition, we summarize how the different long non-coding RNAs involved in each process function. Finally, the shortcomings of long non-coding RNAs as potential therapeutic targets are briefly described. In conclusion, this article provides a clear visualization of the link that exists between long non-coding RNAs and non-alcoholic fatty liver disease.
    Keywords:  long non-coding RNA; mechanism; metabolism; non-alcoholic fatty liver disease
    DOI:  https://doi.org/10.1016/j.clinre.2023.102095
  3. Cancer Cell Int. 2023 Feb 16. 23(1): 28
    Long non-coding RNA signature in colorectal cancer: research progression and clinical application.
    Yudi Wu, Xiangshang Xu.
      Colorectal cancer is one of the top-ranked human malignancies. The development and progression of colorectal cancer are associated with aberrant expression of multiple coding and non-coding genes. Long non-coding RNAs (lncRNAs) have an important role in regulating gene stability as well as gene expression. Numerous current studies have shown that lncRNAs are promising biomarkers and therapeutic targets for colorectal cancer. In this review, we have searched the available literature to list lncRNAs involved in the pathogenesis and regulation of colorectal cancer. We focus on the role of lncRNAs in cancer promotion or suppression, their value in tumor diagnosis, and their role in treatment response and prognosis prediction. In addition, we will discuss the signaling pathways that these lncRNAs are mainly associated with in colorectal cancer. We also summarize the role of lncRNAs in colorectal precancerous lesions and colorectal cancer consensus molecular subgroups. We hope this review article will bring you the latest research progress and outlook on lncRNAs in colorectal cancer.
    Keywords:  Biomarker; Diagnosis; Long non-coding RNA; colorectal cancer
    DOI:  https://doi.org/10.1186/s12935-023-02867-0
  4. Curr Genomics. 2022 Aug 11. 23(4): 246-261
    Long Non-coding RNAs: Pivotal Epigenetic Regulators in Diabetic Retinopathy.
    Zhaoxia Song, Chang He, Jianping Wen, Jianli Yang, Peng Chen.
      Diabetic retinopathy (DR) is a severe complication of diabetes; however, its mechanism is not fully understood. Evidence has recently revealed that long non-coding RNAs (lncRNAs) are abnormally expressed in DR, and lncRNAs may function as pivotal regulators. LncRNAs are able to modulate gene expression at the epigenetic level by acting as scaffolds of histone modification complexes and sponges of binding with microRNAs (miRNAs). LncRNAs are believed to be important epigenetic regulators, which may become beneficial in the diagnosis and therapy of DR. However, the mechanisms of lncRNAs in DR are still unclear. In this review, we summarize the possible functions and mechanisms of lncRNAs in epigenetic regulation to target genes in the progression of DR.
    Keywords:  Diabetic retinopathy; epigenetics; histone modification; lncRNAs; miRNAs; regulator
    DOI:  https://doi.org/10.2174/1389202923666220531105035
  5. Front Plant Sci. 2023 ;14 1131977
    tRNA-derived small RNAs in plant response to biotic and abiotic stresses.
    Chaojun Wang, Weiqiang Chen, Maimaiti Aili, Lei Zhu, Yan Chen.
      tRNA-derived small RNAs (tsRNAs) represent a novel category of small non-coding RNAs and serve as a new regulator of gene expression at both transcriptional and post-transcriptional levels. Growing evidence indicates that tsRNAs can be induced by diverse stimuli and regulate stress-responsive target genes, allowing plants to adapt to unfavorable environments. Here, we discuss the latest developments about the biogenesis and classification of tsRNAs and highlight the expression regulation and potential function of tsRNAs in plant biotic and abiotic stress responses. Of note, we also collect useful bioinformatics tools and resources for tsRNAs study in plants. Finally, we propose current limitations and future directions for plant tsRNAs research. These recent discoveries have refined our understanding of whether and how tsRNAs enhance plant stress tolerance.
    Keywords:  biological function; expression regulation; plant; stress response; tsRNAs
    DOI:  https://doi.org/10.3389/fpls.2023.1131977
  6. Evol Appl. 2023 Feb;16(2): 354-364
    Small RNAs in Cnidaria: A review.
    Yiqian Li, Jerome H L Hui.
      As fundamental components of RNA silencing, small RNA (sRNA) molecules ranging from 20 to 32 nucleotides in length have been found as potent regulators of gene expression and genome stability in many biological processes of eukaryotes. Three major small RNAs are active in animals, including the microRNA (miRNA), short interfering RNA (siRNA), and PIWI-interacting RNA (piRNA). Cnidarians, the sister group to bilaterians, are at a critical phylogenetic node to better model eukaryotic small RNA pathway evolution. To date, most of our understanding of sRNA regulation and its potential contribution to evolution has been limited to a few triploblastic bilaterian and plant models. The diploblastic nonbilaterians, including the cnidarians, are understudied in this regard. Therefore, this review will present the current-known small RNA information in cnidarians to enhance our understanding of the development of the small RNA pathways in early branch animals.
    Keywords:  cnidarians; evolution; small RNAs
    DOI:  https://doi.org/10.1111/eva.13445
  7. RNA. 2023 Feb 15. pii: rna.079388.122. [Epub ahead of print]
    Structural Analysis of MALAT1 long non-coding RNA in cells and in evolution.
    Anais Monroy-Eklund, Colin Taylor, Chase Weidmann, Christina Burch, Alain Laederach.
      Although not canonically polyadenylated, the long non-coding RNA MALAT1 (Metastasis Associated Lung Adenocarcinoma Transcript 1) is stabilized by a highly conserved 76 nucleotide triple helix structure on its 3' end. The entire MALAT1 transcript is over 8,000 nucleotides long in humans. The strongest structural conservation signal in MALAT1 (as measured by co-variation of base-pairs) is in the triple helix structure. Primary sequence analysis of co-variation alone does not reveal the degree of structural conservation of the entire full-length transcript, however. Furthermore, RNA structure is often context dependent; RNA binding proteins that are differentially expressed in different cell types may alter structure. We investigate here the in cell and cell free structures of the full-length human and green monkey (Chlorocebus sabaeus) MALAT1 transcripts in multiple tissue-derived cell lines using SHAPE chemical probing. Our data reveal levels of uniform structural conservation in different cell lines, in cells and cell free, and even between species, despite significant differences in primary sequence. The uniformity of the structural conservation across the entire transcript suggests that, despite seeing co-variation signals only in the triple helix junction of the lncRNA, the rest of the transcript's structure is remarkably conserved at least in primates and across multiple cell types and conditions.
    Keywords:  Green Monkey; MALAT1; Primates; RNA structure; SHAPE
    DOI:  https://doi.org/10.1261/rna.079388.122
  8. Neurochem Res. 2023 Feb 14.
    Targeting Non-Coding RNA for CNS Injuries: Regulation of Blood-Brain Barrier Functions.
    Li Zhang, Wanshan Bai, Lean Sun, Yixing Lin, Mi Tian.
      Central nervous system (CNS) injuries are the most common cause of death and disability around the world. The blood-brain barrier (BBB) is located at the interface between the CNS and the surrounding environment, which protects the CNS from exogenous molecules, harmful agents or microorganisms in the blood. The disruption of BBB is a common feature of CNS injuries and participates in the pathological processes of secondary brain damage. Recently, a growing number of studies have indicated that non-coding RNAs (ncRNAs) play an important role in brain development and are involved in CNS injuries. In this review, we summarize the mechanisms of BBB breakdown after CNS injuries. We also discuss the effects of ncRNAs including long noncoding RNAs (lncRNAs), circular RNAs (circRNAs) and microRNAs (miRNAs) on BBB damage in CNS injuries such as ischemic stroke, traumatic brain injury (TBI), intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH). In addition, we clarify the pharmacotherapies that could regulate BBB function via ncRNAs in CNS injuries, as well as the challenges and perspectives of ncRNAs on modulation of BBB function. Hence, on the basis of these effects, ncRNAs may be developed as therapeutic agents to protect the BBB for CNS injury patients.
    Keywords:  Blood brain barrier; Central nervous system injuries; CircRNA; LncRNA; Therapeutic targets; miRNA
    DOI:  https://doi.org/10.1007/s11064-023-03892-1
  9. Am J Transl Res. 2023 ;15(1): 175-183
    TUG1 aggravates intracerebral hemorrhage injury by inhibiting angiogenesis in an miR-26a-dependent manner.
    Fei Li, Hong-Xiang Jiang, Hui-Kai Zhang, Qian-Xue Chen.
      Long non-coding RNA taurine-upregulated gene 1 (TUG1) plays pivotal roles in angiogenesis, an important mechanism of neural repair after intracerebral hemorrhage (ICH). However, the role of TUG1 in angiogenesis following ICH is not clear. Therefore, in this study, we investigated the role and the underlying mechanism of TUG1 in neurologic impairment and cerebral angiogenesis following ICH. The ICH rat model was established and then rats were injected with TUG1-expressing plasmid (pcDNA-TUG1) or miR-26a mimic, a critical regulator of VEGF-mediated angiogenesis. We confirmed the overexpression of TUG1 and miR-26a by qRT-PCR. The neurological deficits of ICH rats were evaluated by modified neurological severity scores. The expression of angiogenesis markers VEGF and CD31 were examined by immunohistochemistry and western blot. The interaction between TUG1 and miR-26a was determined by luciferase reporter assay. Our results showed that ICH caused a marked upregulation of TUG1 and a significant downregulation of miR-26a. TUG1 overexpression led to the deterioration of neurologic function and inhibited cerebral angiogenesis in ICH rats. In contrast, overexpression of miR-26a alleviated the neurologic damage and promoted cerebral angiogenesis in ICH rats, but these could be attenuated by TUG1 overexpression. Furthermore, TUG1 directly bound to miR-26a and inhibited its expression. Importantly, TUG1 overexpression inhibited the expression of VEGF by targeting miR-26a. In conclusion, our results indicated that TUG1 aggravated ICH-mediated injury by suppressing angiogenesis by downregulating miR-26a. This suggests a rationale for targeting TUG1/miR-26a in the therapy of ICH.
    Keywords:  Angiogenesis; intracerebral hemorrhage; miR-26a; neurological function; taurine-upregulated gene 1
  10. Biophys J. 2023 Feb 10. pii: S0006-3495(22)03201-5. [Epub ahead of print]122(3S1): 422a
    SHAMAN: A mixed solvent molecular dynamics protocol to identify small-molecules binding sites on RNA structural ensembles.
    Francesco Paolo Panei, Paraskevi Gkeka, Massimiliano Bonomi.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.2285
  11. Biophys J. 2023 Feb 10. pii: S0006-3495(22)01487-4. [Epub ahead of print]122(3S1): 67a
    RNA structure controls assembly of multi-layered paraspeckles.
    Wilton T Snead, Krishna Shrinivas, Danial Babaki, Kevin M Weeks, Amy S Gladfelter.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.571
  12. Biosci Rep. 2023 Feb 14. pii: BSR20220313. [Epub ahead of print]
    FinO/ProQ-family proteins: an evolutionary perspective.
    Alexandre Smirnov, Zhen Liao.
      RNA-binding proteins are key actors of post-transcriptional networks. Almost exclusively studied in the light of their interactions with RNA ligands and the associated functional events, they are still poorly understood as evolutionary units. In this review, we discuss the FinO/ProQ family of bacterial RNA chaperones, how they evolve and spread across bacterial populations and what properties and opportunities they provide to their host cells. We reflect on major conserved and divergent themes within the family, trying to understand how the same ancestral RNA-binding fold, augmented with additional structural elements, could yield either highly specialised proteins or, on the contrary, globally acting regulatory hubs with a pervasive impact on gene expression. We also consider dominant convergent evolutionary trends that shaped their RNA chaperone activity and recurrently implicated the FinO/ProQ-like proteins in bacterial DNA metabolism, translation, and virulence. Finally, we offer a new perspective in which FinO/ProQ-family regulators emerge as active evolutionary players with both negative and positive roles, significantly impacting the evolutionary modes and trajectories of their bacterial hosts.
    Keywords:  FinO; ProQ; RNA chaperone; RNA-binding proteins; evolution
    DOI:  https://doi.org/10.1042/BSR20220313
  13. Clin Exp Med. 2023 Feb 14.
    RNA modification in mRNA cancer vaccines.
    Yingxue Mei, Xiang Wang.
      RNA modification is manifested as chemically altered nucleotides, widely exists in diverse natural RNAs, and is closely related to RNA structure and function. Currently, mRNA-based vaccines have received great attention and rapid development as novel and mighty fighters against various diseases including cancer. The achievement of RNA vaccines in clinical application is largely attributed to some methodological innovations including the incorporation of modified nucleotides into the synthetic RNA. The selection of optimal RNA modifications aimed at reducing the instability and immunogenicity of RNA molecules is a very critical task to improve the efficacy and safety of mRNA vaccines. This review summarizes the functions of RNA modifications and their application in mRNA vaccines, highlights recent advances of mRNA vaccines in cancer immunotherapy, and provides perspectives for future development of mRNA vaccines in the context of personalized tumor therapy.
    Keywords:  Combination therapy; Immunogenicity; Immunotherapy; RNA methylation; RNA modification; mRNA cancer vaccine
    DOI:  https://doi.org/10.1007/s10238-023-01020-5
  14. JMA J. 2023 Jan 16. 6(1): 9-15
    RNA Dysmetabolism and Repeat-Associated Non-AUG Translation in Frontotemporal Lobar Degeneration/Amyotrophic Lateral Sclerosis due to C9orf72 Hexanucleotide Repeat Expansion.
    Kohji Mori, Shiho Gotoh, Ryota Uozumi, Tesshin Miyamoto, Shoshin Akamine, Yuya Kawabe, Shinji Tagami, Manabu Ikeda.
      Neuropathological features of frontotemporal dementia and amyotrophic lateral sclerosis (ALS) due to C9orf72 GGGGCC hexanucleotide repeat expansion include early dipeptide repeats, repeat RNA foci, and subsequent TDP-43 pathologies. Since the discovery of the repeat expansion, extensive studies have elucidated the disease mechanism of how the repeat causes neurodegeneration. In this review, we summarize our current understanding of abnormal repeat RNA metabolism and repeat-associated non-AUG translation in C9orf72 frontotemporal lobar degeneration/ALS. For repeat RNA metabolism, we specifically focus on the role of hnRNPA3, the repeat RNA-binding protein, and the EXOSC10/RNA exosome complex, an intracellular RNA-degrading enzyme. In addition, the mechanism of repeat-associated non-AUG translation inhibition via TMPyP4, a repeat RNA-binding compound, is discussed.
    Keywords:  C9orf72; Frontotemporal dementia; RNA metabolism; Repeat-associated non-AUG translation; amyotrophic lateral sclerosis; frontotemporal lobar degeneration
    DOI:  https://doi.org/10.31662/jmaj.2022-0160
  15. Mol Cancer. 2023 Feb 16. 22(1): 32
    Transfer RNA-derived small RNAs in tumor microenvironment.
    Mei Yang, Yongzhen Mo, Daixi Ren, Shun Liu, Zhaoyang Zeng, Wei Xiong.
      Transfer RNAs (tRNAs) are a class of non-coding RNAs responsible for amino acid translocation during protein synthesis and are ubiquitously found in organisms. With certain modifications and under specific conditions, tRNAs can be sheared and fragmented into small non-coding RNAs, also known as tRNA-derived small RNAs (tDRs). With the development of high-throughput sequencing technologies and bioinformatic strategies, more and more tDRs have been identified and their functions in organisms have been characterized. tRNA and it derived tDRs, have been shown to be essential not only for transcription and translation, but also for regulating cell proliferation, apoptosis, metastasis, and immunity. Aberrant expression of tDRs is associated with a wide range of human diseases, especially with tumorigenesis and tumor progression. The tumor microenvironment (TME) is a complex ecosystem consisting of various cellular and cell-free components that are mutually compatible with the tumor. It has been shown that tDRs regulate the TME by regulating cancer stem cells, immunity, energy metabolism, epithelial mesenchymal transition, and extracellular matrix remodeling, playing a pro-tumor or tumor suppressor role. In this review, the biogenesis, classification, and function of tDRs, as well as their effects on the TME and the clinical application prospects will be summarized and discussed based on up to date available knowledge.
    Keywords:  Biomarkers; Therapeutic; Transfer RNAs; Tumor microenvironment (TME); tRFs; tRNA-derived small RNAs (tDRs); tiRNAs
    DOI:  https://doi.org/10.1186/s12943-023-01742-w
  16. Bull Math Biol. 2023 02 13. 85(3): 21
    RNA Secondary Structures with Given Motif Specification: Combinatorics and Algorithms.
    Ricky X F Chen, Christian M Reidys, Michael S Waterman.
      The study of native motifs of RNA secondary structures helps us better understand the formation and eventually the functions of these molecules. Commonly known structural motifs include helices, hairpin loops, bulges, interior loops, exterior loops and multiloops. However, enumerative results and generating algorithms taking into account the joint distribution of these motifs are sparse. In this paper, we present progress on deriving such distributions employing a tree-bijection of RNA secondary structures obtained by Schmitt and Waterman and a novel rake decomposition of plane trees. The key feature of the latter is that the derived components encode motifs of the RNA secondary structures without pseudoknots associated with the plane trees very well. As an application, we present an algorithm (RakeSamp) generating uniformly random secondary structures without pseudoknots that satisfy fine motif specifications on the length and degree of various types of loops as well as helices.
    Keywords:  Helix; Loop; Plane tree; RNA secondary structure; Rake decomposition; Uniform sampling
    DOI:  https://doi.org/10.1007/s11538-023-01128-5
  17. Front Genet. 2023 ;14 1041266
    Expression profiles of lncRNAs and their possible regulatory role in monocrotaline-induced HSOS in rats.
    Mohammed Ismail, Xi Zhang, Reham Taha, Muhanad Elhafiz, Qianwen Zhang, Bashir A Yousef, Xin Huang, Zhenzhou Jiang, Luyong Zhang, Lixin Sun.
      Aims: Long non-coding RNAs (lncRNAs) contribute to the regulation of vital physiological processes and play a role in the pathogenesis of many diseases. Monocrotaline (MCT) can cause large-scale outbreaks of toxic liver disease in humans and animals in the form of hepatic sinusoidal obstruction syndrome (HSOS). Although many experiments have been carried out to explain the pathogenesis of Monocrotaline-induced hepatic sinusoidal obstruction syndrome and to develop treatments for it, no studies have examined the role of Long non-coding RNAs in this condition. This study aimed to investigate the Long non-coding RNAs-mRNA regulation network in Monocrotaline-induced hepatic sinusoidal obstruction syndrome in rats. Main methods: We established a model for MCT-induced hepatic sinusoidal obstruction syndrome, and then carried out microarray for liver tissues of SD rats in a model of early hepatic sinusoidal obstruction syndrome (12 h Monocrotaline treatment vs. control group) to investigate the differentially expressed Long non-coding RNAs and mRNAs in early hepatotoxicity. This was followed by RT-PCR analysis of selected Long non-coding RNAs, which were markedly altered. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome analyses were also conducted. Key findings: 176 Long non-coding RNAs (63 downregulated and 113 upregulated) and 4,221 mRNAs (2,385 downregulated and 1836 upregulated) were differentially expressed in the Monocrotaline-treated group compared to the control group. The biological processes identified in GO enrichment analysis as playing a role in hepatotoxicity were positive regulation of guanosine triphosphate phosphohydrolase, liver development, and the oxidation-reduction process. Pathway analysis revealed that the metabolism pathways, gap junction, and ribosome biogenesis in eukaryotes were closely related to Monocrotaline-induced hepatotoxicity. According to these analyses, LOC102552718 might play an essential role in hepatotoxicity mechanisms by regulating the expression of inositol 1,4,5-trisphosphate receptor-1 (Itpr-1). Significance: This study provides a basis for further research on the molecular mechanisms underlying Monocrotaline-induced hepatotoxicity and its treatment, especially in the early stage, when successful treatment is critical before irreversible liver damage occurs.
    Keywords:  HSOS; Itpr; hepatotoxicity; lncRNA; monocrotaline
    DOI:  https://doi.org/10.3389/fgene.2023.1041266
  18. Lab Invest. 2022 11;pii: S0023-6837(22)00256-2. [Epub ahead of print]102(11): 1182-1191
    Long non-coding RNA DLGAP1-AS1 modulates the development of non-small-cell lung cancer via the microRNA-193a-5p/DTL axis.
    Xudong Pan, Siwen Chen, Lu Ye, Shenjie Xu, Ling Wang, Yi Sun.
      Non-small cell lung cancer (NSCLC) is one of the most malignant cancers worldwide. A growing number of studies have suggested that long noncoding RNAs (lncRNAs) play a key role in the progression of non-small cell lung cancer (NSCLC). Here, we report a novel lncRNA DLGAP1 antisense RNA 1 (DLGAP1-AS1) that exhibits oncogenic properties in NSCLC. The lncRNA DLGAP1-AS1 and denticleless protein homolog (DTL) presented upregulated expression, but microRNA-193a-5p (miR-193a-5p) showed downregulated expression in cancerous tissues of human lung samples from 48 patients with NSCLC. Partial loss of lncRNA DLGAP1-AS1 reduced malignant cell viability, migration, and invasion but induced apoptosis. Dual-luciferase reporter gene, RNA pull-down and RNA binding protein immunoprecipitation assays demonstrated enrichment of lncRNA DLGAP1-AS1 in miR-193a-5p and Argonaute 2, suggesting that lncRNA DLGAP1-AS1 modulated DTL, a putative target of miR-193a-5p. We also found that restoration of miR-193a-5p rescued NSCLC cell biological functions affected by overexpression of lncRNA DLGAP1-AS1. Silencing lncRNA DLGAP1-AS1 was found to reduce the tumorigenesis of NSCLC cells xenografted into nude mice, which was rescued by DTL overexpression. In conclusion, our study highlights a novel regulatory network of the lncRNA DLGAP1-AS1/miR-193a-5p/DTL axis in NSCLC, providing a potential therapeutic strategy for NSCLC.
    DOI:  https://doi.org/10.1038/s41374-022-00831-6
  19. Mol Biol Cell. 2023 Feb 15. mbcE23010004
    Differential nuclear import regulates nuclear RNA inheritance following mitosis.
    Michael D Blower, Wei Wang, Judith Sharp.
      Mitosis results in a dramatic reorganization of chromatin structure in order to promote chromosome compaction and segregation to daughter cells. Consequently, mitotic entry is accompanied by transcriptional silencing and removal of most chromatin-bound RNAs from chromosomes. As cells exit mitosis chromatin rapidly decondenses and transcription restarts as waves of differential gene expression. However, little is known about the fate of chromatin-bound RNAs following cell division. Here we explored whether nuclear RNA from the previous cell cycle is present in G1 nuclei following mitosis. We found that half of all nuclear RNAs are inherited in a transcription-independent manner following mitosis. Interestingly, the snRNA U2 is efficiently inherited by G1 nuclei while lncRNAs NEAT1 and MALAT1 show no inheritance following mitosis. We found that the nuclear protein SAF-A, which is hypothesized to tether RNA to DNA, did not play a prominent role in nuclear RNA inheritance, indicating the mechanism for RNA inheritance may not involve RNA chaperones that have chromatin binding activity. Instead, we observe that the timing of RNA inheritance indicates a select group of nuclear RNAs are reimported into the nucleus after the nuclear envelope has reassembled. Taken together, our work demonstrates that there is a fraction of nuclear RNA from the previous cell cycle that is reimported following mitosis and suggest that mitosis may serve as a time to reset the interaction of lncRNAs with chromatin.
    DOI:  https://doi.org/10.1091/mbc.E23-01-0004
  20. Front Genet. 2023 ;14 1050783
    Integrative analysis of the expression profiles of whole coding and non-coding RNA transcriptomes and construction of the competing endogenous RNA networks for chronic obstructive pulmonary disease.
    Xueyan Feng, Hui Dong, Beibei Li, Liang Yu, Jinyuan Zhu, Caili Lou, Jin Zhang.
      The pathogenesis of Chronic Obstructive Pulmonary Disease (COPD) is implicated in airway inflammation, oxidative stress, protease/anti-protease and emphysema. Abnormally expressed non-coding RNAs (ncRNAs) play a vital role in regulation of COPD occurrence and progression. The regulatory mechanisms of the circRNA/lncRNA-miRNA-mRNA (competing endogenous RNA, ceRNA) networks might facilitate our cognition of RNA interactions in COPD. This study aimed to identified novel RNA transcripts and constructed the potential ceRNA networks of COPD patients. Total transcriptome sequencing of the tissues from patients with COPD (COPD) (n = 7) and non-COPD control subjects (Normal) (n = 6) was performed, and the expression profiles of differentially expressed genes (DEGs), including mRNAs, lncRNAs, circRNAs, and miRNAs, were analyzed. The ceRNA network was established based on the miRcode and miRanda databases. Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), Gene Set Enrichment Analysis (GSEA), and Gene set variation analysis (GSVA) were implemented for functional enrichment analysis of DEGs. Finally, CIBERSORTx was extracted to analyze the relevance between hub genes and various immune cells.The Starbase and JASPAR databases were used to construct hub-RNA binding proteins (RBPs) and lncRNA-transcription factor (TF) interaction networks. A total of 1,796 mRNAs, 2,207 lncRNAs, and 11 miRNAs showed differentially expression between the lung tissue samples from the normal and COPD groups. Based on these DEGs, lncRNA/circRNA-miRNA-mRNA ceRNA networks were constructed respectively. In addition, ten hub genes were identified. Among them, RPS11, RPL32, RPL5, and RPL27A were associated with the proliferation, differentiation, and apoptosis of the lung tissue. The biological function revealed that TNF-α via NF-kB and IL6/JAK/STAT3 signaling pathways were involved in COPD. Our research constructed the lncRNA/circRNA-miRNA-mRNA ceRNA networks, filtrated ten hub genes may regulate the TNF-α/NF-κB, IL6/JAK/STAT3 signally pathways, which indirectly elucidated the post-transcriptional regulation mechanism of COPD and lay the foundation for excavating the novel targets of diagnosis and treatment in COPD.
    Keywords:  MicroRNA (miRNA); chronic obstructive pulmonary disease (COPD); circular RNA (circRNA); competing endogenous RNAs (ceRNA) network; long non-coding RNA (IncRNA); messenger RNA (mRNA)
    DOI:  https://doi.org/10.3389/fgene.2023.1050783
  21. Biophys J. 2023 Feb 10. pii: S0006-3495(22)03308-2. [Epub ahead of print]122(3S1): 443a
    Understanding cooperativity effects in RNA structure probing experiments.
    Emma Bose, Alisha Jones.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.2392
  22. Lab Invest. 2021 09;pii: S0023-6837(22)00574-8. [Epub ahead of print]101(9): 1118-1129
    The lncRNA XIST/miR-150-5p/c-Fos axis regulates sepsis-induced myocardial injury via TXNIP-modulated pyroptosis.
    Xin Wang, Xing-Liang Li, Li-Jie Qin.
      Myocardial injury is a severe complication of sepsis and contributes substantially to the death of critically ill patients. Long non-coding RNAs (lncRNAs) participate in the pathogenesis of sepsis-induced myocardial injury. In this study, we investigated the role of lncRNA X-inactive specific transcript (XIST) in septic myocardial injury and explored its mechanism. Lipopolysaccharide (LPS)-stimulated H9C2 cells and rats subjected to cecal ligation and puncture (CLP) were used as the in vitro and in vivo models. After exposure to LPS, XIST and c-Fos levels were upregulated, but miR-150-5p was downregulated in H9C2 cardiomyocytes and myocardial tissues. XIST affected viability, apoptosis, and pyroptosis in LPS-challenged H9C2 cells. Moreover, XIST knockdown attenuated LPS-induced injury in H9C2 cells by targeting the miR-150-5p/c-Fos axis. c-Fos could bound to the promoter of the TXNIP/XIST gene and enhanced TXNIP/XIST expression. Silencing of XIST improved cardiac function and survival rate and reduced apoptosis and pyroptosis by regulating the miR-150-5p/c-Fos axis in septic rats in vivo. Taken together, our data show that XIST/miR-150-5p/c-Fos axis affected septic myocardial injury, which may indicate a novel therapeutic strategy for sepsis-induced myocardial injury. The authors show that the long non-coding RNA XIST, together with the microRNA miR-150-5p and c-Fos, regulate sepsis-induced myocardial injury via the TXNIP pathway. XIST affects pyroptosis, and XIST knockdown attenuates lipopolysaccharide-induced injury. These results suggest that the XIST/miR-150-5p/c-Fos axis may be a novel therapeutic strategy for sepsis-induced myocardial injury.
    DOI:  https://doi.org/10.1038/s41374-021-00607-4
  23. Plant Cell. 2023 Feb 16. pii: koad044. [Epub ahead of print]
    The covalent nucleotide modifications within plant mRNAs: What we know, how we find them, and what should be done in the future.
    Wil Prall, Diep R Ganguly, Brian D Gregory.
      Although covalent nucleotide modifications were first identified on the bases of transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), a number of these epitranscriptome marks have also been found to occur on the bases of messenger RNAs (mRNAs). These covalent mRNA features have been demonstrated to have various and significant effects on the processing (e.g. splicing, polyadenylation, etc.) and functionality (e.g. translation, transport, etc.) of these protein-encoding molecules. Here, we focus our attention on the current understanding of the collection of covalent nucleotide modifications known to occur on mRNAs in plants, how they are detected and studied, and the most outstanding future questions of each of these important epitranscriptomic regulatory signals.
    DOI:  https://doi.org/10.1093/plcell/koad044
  24. Signal Transduct Target Ther. 2023 Feb 17. 8(1): 69
    Targeting epigenetic regulators to overcome drug resistance in cancers.
    Nan Wang, Ting Ma, Bin Yu.
      Drug resistance is mainly responsible for cancer recurrence and poor prognosis. Epigenetic regulation is a heritable change in gene expressions independent of nucleotide sequence changes. As the common epigenetic regulation mechanisms, DNA methylation, histone modification, and non-coding RNA regulation have been well studied. Increasing evidence has shown that aberrant epigenetic regulations contribute to tumor resistance. Therefore, targeting epigenetic regulators represents an effective strategy to reverse drug resistance. In this review, we mainly summarize the roles of epigenetic regulation in tumor resistance. In addition, as the essential factors for epigenetic modifications, histone demethylases mediate the histone or genomic DNA modifications. Herein, we comprehensively describe the functions of the histone demethylase family including the lysine-specific demethylase family, the Jumonji C-domain-containing demethylase family, and the histone arginine demethylase family, and fully discuss their regulatory mechanisms related to cancer drug resistance. In addition, therapeutic strategies, including small-molecule inhibitors and small interfering RNA targeting histone demethylases to overcome drug resistance, are also described.
    DOI:  https://doi.org/10.1038/s41392-023-01341-7
  25. Am J Cancer Res. 2023 ;13(1): 227-235
    Long non-coding RNA PSMG3 Antisense RNA 1 is correlated with oral squamous cell carcinoma and regulates cancer cell proliferation by targeting premature microRNA-141.
    Shaobo Ouyang, Feng Xuan, Xianhua Zhang, Wei Yuan, Xin Fan, Jun Wang.
      Oral squamous cell carcinoma (OSCC) is common worldwide. In this study, the interaction of microRNA-141 (miR-141) with long non-coding RNA (lncRNA) PSMG3 Antisense RNA 1 (PSMG3-AS1) in OSCC was explored. RT-qPCR was used to analyze the expression of PSMG3-AS1 and miR-141 (both mature and premature) in OSCC. Nuclear fractionation assay was applied to detect PSMG3-AS1 in subcellular locations. RNA pull-down assay was performed to evaluate the binding of miR-141 to PSMG3-AS1. Overexpression assay followed by RT-qPCR was performed to explore the role of PSMG3-AS1 in maturation of miR-141. The function of PSMG3-AS1 and miR-141 in regulating OSCC cell proliferation was assessed by BrdU assay. The results showed that PSMG3-AS1 was highly upregulated in OSCC and miR-141 was downregulated in OSCC. However, no alteration in the expression of premature miR-141 was observed in OSCC. Premature miR-141 was found to directly bind to PSMG3-AS1. Overexpression of PSMG3-AS1 suppressed the maturation of miR-141. PSMG3-AS1 increased OSCC cell proliferation and tumor growth and suppressed the inhibitory role of miR-141 in cell proliferation and tumor growth. Therefore, PSMG3-AS1 may inhibit the maturation of miR-141 to promote OSCC cell proliferation.
    Keywords:  PSMG3-AS1; cell proliferation; miR-141; miRNA maturation; oral squamous cell carcinoma
  26. Lab Invest. 2021 Jul;pii: S0023-6837(22)00235-5. [Epub ahead of print]101(7): 908-920
    LncRNA SLCO4A1-AS1 modulates colon cancer stem cell properties by binding to miR-150-3p and positively regulating SLCO4A1.
    Kun Wu, Ting Xu, Xudong Song, Jie Shen, Shutao Zheng, Li Zhang, Guoquan Tao, Baofei Jiang.
      Long non-coding RNAs (lncRNAs) play important roles in a range of different human cancers. However, the role of lncRNA solute carrier organic anion transporter family member 4A1-AS1 (SLCO4A1-AS1) in colon cancer remains enigmatic. Hence, we aimed to explore the specific role of SLCO4A1-AS1 in colon cancer stem cells. Colon cancer-related differentially expressed lncRNA and mRNA were screened using microarray-based analysis, and the expression of SLCO4A1-AS1 and SLCO4A1 in colon cancer tissues was determined using reverse transcription quantitative polymerase chain reaction and western blot analysis. The interaction among SLCO4A1-AS1, microRNA-150-3p (miR-150-3p) and SLCO4A1 was verified using dual-luciferase reporter assay, RNA immunoprecipitation and RNA pull-down. Moreover, SLCO4A1-AS1, miR-150-3p and/or SLCO4A1 were overexpressed or depleted in colon cancer cells to detect their effects on migration, invasion, sphere formation, apoptosis and tumorigenesis abilities of colon cancer stem CD133+CD44+ cells using both in vitro and in vivo assays. SLCO4A1-AS1 and SLCO4A1 were screened as the differentially expressed lncRNA and mRNA in colon cancer tissues. SLCO4A1-AS1 was confirmed to competitively bind to miR-150-3p to elevate SLCO4A1 expression. Moreover, knockdown of SLCO4A1-AS1 decreased SLCO4A1 expression, thus inhibiting cell migration, invasion, sphere formation, and tumorigenesis abilities and enhancing the apoptosis of CD133+CD44+ cells. Collectively, these findings provide evidence demonstrating that depleting SLCO4A1-AS1 competitively binds to miR-150-3p, which downregulates SLCO4A1 expression, thus hindering colon cancer progression. This study reports that long non-coding RNA lncRNA SLCO4A1-AS1 regulates the characteristics of colon cancer stem cells. Moreover, SLCO4A1 targets miR-150-3p. LncRNA SLCO4A1-AS1 can be used as ceRNA to adsorb miR-150-3p and thus affect the expression of SLCO4A1. Mechanistically, miR-150-3p can downregulate SLCO4A1, thereby inhibiting migration, invasion, spheroidization and tumor formation of colon cancer stem cells. This study lays a theoretical foundation for in-depth understanding of the pathogenesis of colon cancer and points to new therapeutic targets.
    DOI:  https://doi.org/10.1038/s41374-021-00577-7
  27. Biophys J. 2023 Feb 10. pii: S0006-3495(22)02746-1. [Epub ahead of print]122(3S1): 327a
    RNA structure directs the targeting specificity of Cas13d.
    Ilya Finkelstein.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.1830
  28. RNA. 2023 Feb 13. pii: rna.079575.122. [Epub ahead of print]
    Transfer RNA halves are found as nicked tRNAs in cells: evidence that nicked tRNAs regulate expression of an RNA repair operon.
    Xinguo Chen, Sandra L Wolin.
      Transfer RNA fragments are proposed to regulate numerous processes in eukaryotes, including translation inhibition, epigenetic inheritance and cancer. In the bacterium Salmonella enterica serovar Typhimurium, 5' tRNA halves ending in 2', 3' cyclic phosphate are proposed to bind the RtcR transcriptional activator, resulting in transcription of an RNA repair operon. However, since 5' and 3' tRNA halves can remain base paired after cleavage, the 5' tRNA halves could potentially bind RtcR as nicked tRNAs. Here we report that nicked tRNAs are ligands for RtcR. By isolating RNA from bacteria under conditions that preserve base pairing, we show that many tRNA halves are in the form of nicked tRNAs. Using a circularly permuted tRNA that mimics a nicked tRNA, we show that nicked tRNA ending in 2', 3' cyclic phosphate is a better ligand for RtcR than the corresponding 5' tRNA half. In human cells, we show that some tRNA halves similarly remain base paired as nicked tRNAs following cleavage by anticodon nucleases. Our work supports a role for the RNA repair operon in repairing nicked tRNAs and has implications for the functions proposed for tRNA fragments in eukaryotes.
    Keywords:  RNA repair; nicked tRNAs; tRNA fragments
    DOI:  https://doi.org/10.1261/rna.079575.122
  29. Pathol Oncol Res. 2023 ;29 1610870
    Long non-coding RNA MYU promotes ovarian cancer cell proliferation by sponging miR-6827-5p and upregulating HMGA1.
    Shaoyu Wang, Qiaomei Zheng, Jinhua Wang, Shaozhan Chen, Lihong Chen.
      Background: Long non-coding RNAs (lncRNAs) have been confirmed to play vital roles in tumorigenesis. LncRNA MYU has recently been reported as an oncogene in several kinds of tumors. However, MYU's expression status and potential involvement in ovarian cancer (OC) remain unclear. In this study, we explored the underlying role of MYU in OC. Methods and results: The expression of MYU was upregulated in OC tissues, and MYU's overexpression was significantly correlated with the FIGO stage and lymphatic metastasis. Knockdown of MYU inhibited cell proliferation in SKOV3 and A2780 cells. Mechanistically, MYU directly interacted with miR-6827-5p in OC cells; HMGA1 is a downstream target gene of miR-6827-5p. Furthermore, MYU knockdown increased the expression of miR-6827-5p and decreased the expression of HMGA1. Restoration of HMGA1 expression reversed the influence on cell proliferation caused by MYU knockdown. Conclusion: MYU functions as a ceRNA that positively regulates HMGA1 expression by sponging miR-6827-5p in OC cells, which may provide a potential target and biomarker for the diagnosis or prognosis of OC.
    Keywords:  HMGA1; MYU; lncRNA; miR-6827-5p; ovarian cancer
    DOI:  https://doi.org/10.3389/pore.2023.1610870
  30. JCI Insight. 2023 Feb 14. pii: e160745. [Epub ahead of print]
    The long non-coding RNA THBS1-AS1 promotes cardiac fibroblast activation in cardiac fibrosis by regulating TGFBR1.
    Junteng Zhou, Geer Tian, Yue Quan, Qihang Kong, Fangyang Huang, Junli Li, Wenchao Wu, Yong Tang, Zhichao Zhou, Xiaojing Liu.
      Cardiac fibrosis is associated with an adverse prognosis in cardiovascular disease, which results in a decreased cardiac compliance and ultimately heart failure. Recent studies have identified the role of long non-coding RNA (lncRNA) in cardiac fibrosis. However, the functions of many lncRNAs in cardiac fibrosis remain to be characterized. Through a whole-transcriptome sequencing and bioinformatics analysis on a mouse model of pressure overload-induced cardiac fibrosis, we screened a key lncRNA termed thrombospondin 1 antisense 1 (THBS1-AS1), which was positively associated with cardiac fibrosis. In vitro functional studies demonstrated that the silencing of THBS1-AS1 ameliorated TGF-β1 effects on cardiac fibroblasts (CFs) activation and the overexpression of THBS1-AS1 displayed the opposite effect. A mechanistic study revealed that THBS1-AS1 could sponge miR-221/222 to regulate the expression of TGFBR1. Moreover, under TGF-β1 stimulation, the forced expression of miR-221/222 or the knockdown TGFBR1 significantly reversed the THBS1-AS1 overexpression induced further cardiac fibroblast activation. In vivo, specific knockdown of THBS1-AS1 in activated cardiac fibroblasts significantly alleviated transverse aorta constriction (TAC)-induced cardiac fibrosis in mice. Finally, we demonstrated that the human THBS1-AS1 can also affect the activation of cardiac fibroblasts by regulating TGFBR1. In conclusion, this study reveals that lncRNA THBS1-AS1 is a novel regulator of cardiac fibrosis and may serve as a potential target for the treatment of cardiac fibrosis.
    Keywords:  Cardiology; Cardiovascular disease; Fibrosis; Noncoding RNAs
    DOI:  https://doi.org/10.1172/jci.insight.160745
  31. DNA Cell Biol. 2023 Feb 16.
    Diverse Functions of MiR-425 in Human Cancer.
    Zhichao Wang, Wenjie Xie, Hongzai Guan.
      miRNAs are a type of small endogenous noncoding RNA composed of 20-22 nucleotides that can regulate gene expression by targeting the 3' untranslated region of mRNA. Many investigations have discovered that miRNAs have a role in the development and progression of human cancer. Several aspects of tumor development are affected by miR-425, including growth, apoptosis, invasion, migration, epithelial-mesenchymal transition, and drug resistance. In this article, we discuss the properties and research development of miR-425, focusing on the regulation and function of miR-425 in various cancers. Furthermore, we discuss the clinical implications of miR-425. This review may broaden our horizon for better understanding the role of miR-425 as biomarkers and therapeutic targets in human cancer.
    Keywords:  biomarker; cancer; mechanism; miR-425; signal pathways
    DOI:  https://doi.org/10.1089/dna.2022.0557
  32. Biophys J. 2023 Feb 10. pii: S0006-3495(22)01283-8. [Epub ahead of print]122(3S1): 27a
    Modeling of RNA-only structures.
    Rhiju Das.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.367
  33. J Inorg Biochem. 2023 Jan 31. pii: S0162-0134(23)00035-1. [Epub ahead of print]242 112153
    The structural features of the ligand-free moaA riboswitch and its ion-dependent folding.
    Fabio Amadei, María Reichenbach, Sofia Gallo, Roland K O Sigel.
      Riboswitches are structural elements of mRNA involved in the regulation of gene expression by responding to specific cellular metabolites. To fulfil their regulatory function, riboswitches prefold into an active state, the so-called binding competent form, that guarantees metabolite binding and allows a consecutive refolding of the RNA. Here, we describe the folding pathway to the binding competent form as well as the ligand free structure of the moaA riboswitch of E. coli. This RNA proposedly responds to the molybdenum cofactor (Moco), a highly oxygen-sensitive metabolite, essential in the carbon and sulfur cycles of eukaryotes. K+- and Mg2+-dependent footprinting assays and spectroscopic investigations show a high degree of structure formation of this RNA already at very low ion-concentrations. Mg2+ facilitates additionally a general compaction of the riboswitch towards its proposed active structure. We show that this fold agrees with the earlier suggested secondary structure which included also a long-range tetraloop/tetraloop-receptor like interaction. Metal ion cleavage assays revealed specific Mg2+-binding pockets within the moaA riboswitch. These Mg2+ binding pockets are good indicators for the potential Moco binding site, since in riboswitches, Mg2+ was shown to be necessary to bind phosphate-carrying metabolites. The importance of the phosphate and of other functional groups of Moco is highlighted by binding assays with tetrahydrobiopterin, the reduced and oxygen-sensitive core moiety of Moco. We demonstrate that the general molecular shape of pterin by its own is insufficient for the recognition by the riboswitch.
    Keywords:  Footprinting; Molybdenum cofactor; RNA; Riboswitch; Terbium(III) cleavage
    DOI:  https://doi.org/10.1016/j.jinorgbio.2023.112153
  34. Mol Plant Pathol. 2023 Feb 16.
    vsiRNA18 derived from tobacco curly shoot virus can regulate virus infection in Nicotiana benthamiana.
    Rui Wu, Gentu Wu, Yongjie Huang, Haolan Zhang, Jiaxin Tang, Mingjun Li, Ling Qing.
      Virus-derived small interfering RNAs (vsiRNAs) play important roles in regulating host endogenous gene expression to promote virus infection and induce RNA silencing to suppress virus infection. However, to date, how vsiRNAs affect geminivirus infection in host plants has been less studied. In this study, we found that tobacco curly shoot virus (TbCSV)-derived vsiRNA18 (TvsiRNA18) can regulate TbCSV infection in Nicotiana benthamiana plants. The virus-mediated small RNA expression system and stable transformation technique were used to clarify the molecular role of TvsiRNA18 in TbCSV infection. The results indicate that TvsiRNA18 can aggravate disease symptoms in these plants and enhance viral DNA accumulation. ATP-dependent RNA helicase (ATP-dRH) was proven to be a target of TvsiRNA18, and down-regulation of ATP-dRH in plants was shown to induce virus-like leaf curling symptoms and increase TbCSV infection. These results suggest that TvsiRNA18 is an important regulator of TbCSV infection by suppressing ATP-dRH expression. This is the first report to demonstrate that TbCSV-derived vsiRNA can target host endogenous genes to affect symptom development, which helps to reveal the molecular mechanism of symptom occurrence after the virus infects the host.
    Keywords:  ATP-dependent RNA helicase; RNA silencing; tobacco curly shoot virus; virus-derived small interfering RNAs
    DOI:  https://doi.org/10.1111/mpp.13310
  35. Adv Colloid Interface Sci. 2023 Feb 07. pii: S0001-8686(23)00022-2. [Epub ahead of print]313 102855
    Characterization of structures and molecular interactions of RNA and lipid carriers using atomic force microscopy.
    Jingyi Wang, Jiawen Zhang, Sijia Li, Dengfeng Liu, Akhilesh Bhambhani, Hongbo Zeng.
      Ribonucleic acid (RNA) and lipid are essential biomolecules in many biological processes, and hold a great prospect for biomedical applications, such as gene therapy, vaccines and therapeutic drug delivery. The characterization of morphology and intra-/inter-molecular interactions of RNA and lipid molecules is critical for understanding their functioning mechanisms. Atomic force microscopy (AFM) is a sophisticated technique for characterizing biomolecules featured by its piconewton force sensitivity, sub-nanometer spatial resolution, and flexible operation conditions in both air and liquid. The goal of this review is to highlight the representative and outstanding discoveries of the characterization of RNA and lipid molecules through morphology identification, physicochemical property determination and intermolecular force measurements by AFM. The first section introduces the AFM imaging of RNA molecules to obtain high-resolution morphologies and nanostructures in air and liquid, followed by the discussion of employing AFM force spectroscopy in understanding the nanomechanical properties and intra-/inter-molecular interactions of RNA molecules, including RNA-RNA and RNA-biomolecule interactions. The second section focuses on the studies of lipid and RNA encapsulated in lipid carrier (RNA-lipid) by AFM as well as the sample preparation and factors influencing the morphology and structure of lipid/RNA-lipid complexes. Particularly, the nanomechanical properties of lipid and RNA-lipid characterized by nanomechanical imaging and force measurements are discussed. The future perspectives and remaining challenges on the characterization of RNA and lipid offered by the versatile AFM techniques are also discussed. This review provides useful insights on the characterization of RNA and lipids nanostructures along with their molecular interactions, and also enlightens the application of AFM techniques in investigating a broad variety of biomolecules.
    Keywords:  Atomic force microscopy; Imaging; Lipid; RNA; Single-molecule force spectroscopy
    DOI:  https://doi.org/10.1016/j.cis.2023.102855
  36. Lab Invest. 2021 09;pii: S0023-6837(22)00577-3. [Epub ahead of print]101(9): 1153-1165
    LncRNA UCC promotes epithelial-mesenchymal transition via the miR-143-3p/SOX5 axis in non-small-cell lung cancer.
    Ri Chen, Chunfan Zhang, Yuanda Cheng, Shaoqiang Wang, Hang Lin, Heng Zhang.
      Long non-coding RNAs (lncRNAs) have been found to play regulatory roles in cancers; for example, UCC was reported to promote colorectal cancer progression. However, the function of UCC in non-small-cell lung cancer (NSCLC) remains unclear. Therefore, mRNA and protein levels were assessed using qPCR and western blots. Cell viability was assessed by colony-formation assays. The interaction between lncRNAs and miRNAs was detected by dual-luciferase reporter and RIP assays. The tumorigenesis of NSCLC cells in vivo was determined by xenograft assays. LncRNA UCC was highly expressed in both NSCLC tissues and cells. Knockdown of UCC expression suppressed the proliferation of NSCLC cells. In addition, a dual-luciferase reporter system and RIP assays showed that UCC specifically bound to miR-143-3p and acted as a sponge of miR-143-3p in NSCLC cells. The miR-143-3p inhibitor rescued the inhibitory effect of sh-UCC on the proliferation of NSCLC cells. Moreover, miR-143-3p and UCC showed opposite effects on the expression of SOX5, which promoted EMT in NSCLC cells. In addition, in a mouse model, knockdown of UCC expression alleviated EMT and NSCLC progression in vivo, which was consistent with the in vitro results. In the current study, we found that UCC induced the proliferation and migration of NSCLC cells both in vitro and in vivo by inducing the expression of SOX5 via miR-143-3p and subsequently promoted EMT in NSCLC. The long non-coding RNA UCC acts as a competing endogenous RNA of miR-143-3p and upregulates SOX5 by absorbing miR-143-3p, resulting in proliferation and migration of non-small-cell lung cancer (NSCLC) cells both in vitro and in vivo. UCC enhances carcinogenesis of NSCLC cells via the miR-143-3p/SOX5 axis, which may function as a novel target for NSCLC treatment.
    DOI:  https://doi.org/10.1038/s41374-021-00586-6
  37. Biol Chem. 2023 Feb 14.
    Neuronal stress granules as dynamic microcompartments: current concepts and open questions.
    Anna-Carina Söhnel, Roland Brandt.
      Stress granules are cytosolic, membraneless RNA-protein complexes that form in the cytosol in response to various stressors. Stress granules form through a process termed liquid-liquid phase separation, which increases the local concentration of RNA and protein within the granules, creates dynamic sorting stations for mRNAs and associated proteins, and modulates the availability of mRNA for protein translation. We introduce the concept that neuronal stress granules act as dynamic cytosolic microcompartments in which their components differentially cycle in and out, monitoring the cellular environment. We discuss that neuronal stress granules have distinctive features and contain substructures in which individual components interact transiently. We describe that neuronal stress granules modulate protein expression at multiple levels and affect the proteoform profile of the cytoskeletal protein tau. We argue that a better knowledge of the regulation of stress granule dynamics in neurons and the modulation of their material state is necessary to understand their function during physiological and pathological stress responses. Finally, we delineate approaches to determine the behavior and regulation of critical stress granule organizers and the physical state of stress granules in living neurons.
    Keywords:  RNA-protein complex; condensate; liquid-liquid phase separation; mRNA; tau; translation
    DOI:  https://doi.org/10.1515/hsz-2022-0302
  38. Funct Integr Genomics. 2023 Feb 15. 23(1): 61
    Application value of circulating LncRNA in diagnosis, treatment, and prognosis of breast cancer.
    Ming Li, Yuan Zhao, Huimin Li, Xuming Deng, Miaomiao Sheng.
      Breast cancer is the malignant tumor with the highest incidence in women worldwide. It is highly heterogeneous, has a high incidence of drug resistance, recurrence, and metastasis, and is one of the malignant tumors with the highest mortality rate. The early diagnosis, treatment monitoring, and prognosis assessment of breast cancer are the key factors affecting the survival of patients. However, due to the lack of specific biomarkers, breast cancer is still an essential factor affecting women's quality of life and physical and mental health. Long non-coding RNA can regulate various genes and different signaling pathways and plays an essential role in the occurrence and development of tumors. Recent studies have found that the abnormal expression of circulating long non-coding RNA in serum, saliva, and other biological body fluids plays a significant role in early diagnosis, pathological classification, stage, therapeutic effect monitoring, and prognosis evaluation of breast cancer. This article will review the potential application value of circulating lncRNA in breast cancer.
    Keywords:  Breast cancer; Circulating lncRNA; Diagnosis; Prognosis; Treatment
    DOI:  https://doi.org/10.1007/s10142-023-00983-8
  39. Int J Biol Sci. 2023 ;19(3): 967-980
    Long non-coding RNA BC002811 Promotes Gastric Cancer Metastasis by Regulating SOX2 Binding to the PTEN Promoter.
    Xiaocong Lin, Guodan Li, Xiuwen Yan, Weiyu Fu, Jie Ruan, Hang Ding, Huajun Yu, Xiaoyi Chen, Liubo Lan, Yong Dai, Kai Pan, Xinguang Liu, Haitao Zhang.
      There is increasing evidence that long non-coding RNAs (lncRNAs) are involved in the pathogenesis and progression of gastric cancer (GC), however, the underlying mechanisms remain poorly understood. In this study, we identified lncRNA BC002811 as a critical regulator of GC development and progression. BC002811 was upregulated in GC tissues and cell lines, and that high expression of BC002811 was indicative of a reduction in overall survival of GC patients. Our research reveals that BC002811 promoted GC cell proliferation, migration, invasion, and inhibition of apoptosis in vitro, as well as accelerated tumor growth and metastasis in vivo. We also found that BC002811 upregulated MMP2 and MMP9 and promoted GC cell metastasis partially through downregulating PTEN expression. BC002811 may act as a molecular decoy for the transcription factor SOX2, thereby inhibiting the transcription of PTEN by blocking SOX2 binding to the PTEN promoter. Our study advances the understanding of the role of BC002811 in the pathogenesis of GC and provides new molecular targets for therapeutic intervention against GC metastasis.
    Keywords:  Gastric cancer; Long non-coding RNA; PTEN; Tumor metastasis
    DOI:  https://doi.org/10.7150/ijbs.76407
  40. Oxid Med Cell Longev. 2023 ;2023 3308725
    MBNL1-AS1 Promotes Hypoxia-Induced Myocardial Infarction via the miR-132-3p/RAB14/CAMTA1 Axis.
    Yanbing Li, Min Zong, Xiaonan Guan, Xuejiao Wu, Guiling Ma, Yu Wei, Zhi Li.
       Background: Mounting evidence have indicated that long noncoding RNA (lncRNA) muscleblind like splicing regulator 1 antisense RNA 1 (MBNL1-AS1) play a crucial regulatory role in cardiovascular disease, myocardial infarction (MI) included. In this research, we sought to probe into the biological function and potential mechanism of MBNL1-AS1 in MI.
    Methods: Cardiomyocytes were treated under hypoxic conditions for 0-12 h. Functional assays including CCK-8 and flow cytometry were performed to assess hypoxia-stimulated cardiomyocyte viability and apoptosis, respectively. Moreover, bioinformatics analysis and mechanical assays were conducted to reveal the competitive endogenous RNA (ceRNA) mechanism of MBNL1-AS1.
    Results: The upregulation of MBNL1-AS1 was found in hypoxia-stimulated cardiomyocytes. Functionally, the downregulation of MBNL1-AS1 dramatically promoted hypoxia-induced cardiomyocyte viability and inhibited apoptosis. Mechanistically, miR-132-3p bound to MBNL1-AS1 in hypoxia-induced cardiomyocytes, and miR-132-3p directly targeted RAB14, member RAS oncogene family (RAB14) and calmodulin binding transcription activator 1 (CAMTA1). Furthermore, MBNL1-AS1 upregulates the expression of RAB14 and CAMTA1 in hypoxia-stimulated cardiomyocytes via targeting miR-132-3p.
    Conclusions: The current study revealed the critical role of the MBNL1-AS1/miR-132-3p/RAB14/CAMTA1 axis in MI, indicating MBNL1-AS1 as an innovative therapeutic target for MI.
    DOI:  https://doi.org/10.1155/2023/3308725
  41. Mol Microbiol. 2023 Feb 14.
    The RNA-RNA interactome between a phage and its satellite virus reveals a small RNA that differentially regulates gene expression across both genomes.
    Drew T Dunham, Angus Angermeyer, Kimberley D Seed.
      Satellite viruses are present across all domains of life, defined as sub-viral parasites that require infection by another virus for satellite progeny production. Phage satellites exhibit various regulatory mechanisms to manipulate phage gene expression to the benefit of the satellite, redirecting resources from the phage to the satellite, and often inhibiting phage progeny production. While small RNAs (sRNAs) are well documented as regulators of prokaryotic gene expression, they have not been shown to play a regulatory role in satellite-phage conflicts. Vibrio cholerae encodes the phage inducible chromosomal island-like element (PLE), a phage satellite, to defend itself against the lytic phage ICP1. Here we use Hi-GRIL-seq to identify a complex RNA-RNA interactome between PLE and ICP1. Both inter- and intra-genome RNA interactions were detected, headlined by the PLE sRNA, SviR. SviR is involved in regulating both PLE and ICP1 gene expression uniquely, decreasing ICP1 target translation and affecting PLE transcripts. The striking conservation of SviR across all known PLEs suggests the sRNA is deeply rooted in the PLE-ICP1 conflict and implicates sRNAs as unidentified regulators of gene expression in phage-satellite interactions.
    Keywords:  Bacterial RNA; Bacteriophage; Regulatory RNA; Satellite viruses; Vibrio cholerae
    DOI:  https://doi.org/10.1111/mmi.15046
  42. Front Immunol. 2023 ;14 1118483
    Regulation of mRNA stability contributes to the function of innate lymphoid cells in various diseases.
    Yuanyu Deng, Saiyu Shi, Jie Luo, Yiwei Zhang, Hui Dong, Xian Wang, Jian Zhou, Zhiyuan Wei, Jiahui Li, Chen Xu, Shuai Xu, Yi Sun, Bing Ni, Yuzhang Wu, Di Yang, Chao Han, Yi Tian.
      Innate lymphoid cells (ILCs) are important subsets of innate immune cells that regulate mucosal immunity. ILCs include natural killer cells, innate lymphoid cells-1 (ILC1s), ILC2s, and ILC3s, which have extremely important roles in the immune system. In this review, we summarize the regulation of mRNA stability mediated through various factors in ILCs (e.g., cytokines, RNA-binding proteins, non-coding RNAs) and their roles in mediating functions in different ILC subsets. In addition, we discuss potential therapeutic targets for diseases such as chronic obstructive pulmonary disease, cancer, and pulmonary fibrosis by regulation of mRNA stability in ILCs, which may provide novel directions for future clinical research.
    Keywords:  ILCs; RBPs; cytokines; mRNA stability; non-coding RNA
    DOI:  https://doi.org/10.3389/fimmu.2023.1118483
  43. Am J Cancer Res. 2023 ;13(1): 293-306
    MiR-181a-5p inhibits uveal melanoma development by targeting GNAQ and AKT3.
    Rui Wang, Houda Tahiri, Chun Yang, Solange Landreville, Sonia Callejo, Pierre Hardy.
      Uveal melanoma (UM) is the most common primary intraocular malignant tumor type in adults. Even after the treatment of the ocular tumor, the prognosis of patients with metastasis remains poor. Hence, an urgent unmet need exists to identify novel approaches to treat advanced UM. Previous studies have revealed G subunit alpha Q and alpha 11 (GNAQ/11) mutations in more than 85% of patients with UM, thus indicating the importance of GNAQ and downstream signaling pathways in UM occurrence. Here, we demonstrate that microRNA (miR)-181a-5p, a small non-coding RNA, effectively inhibited the viability, proliferation, and colony formation but induced apoptosis of UM cells. Furthermore, silencing GNAQ or AKT3 mimicked the anti-UM effects of miR-181a-5p, whereas overexpression of GNAQ or AKT3 rescued the anti-UM effects induced by miR-181a-5p. In addition, miR-181a-5p had a stronger effect in decreasing the viability of GNAQ mutant than GNAQ wild-type cells. Moreover, miR-181a-5p suppressed the total expression and phosphorylation of members of the ERK and PI3K/AKT/mTOR signaling pathways. Importantly, miR-181a-5p potently inhibited the growth of UM xenografts in nude mice. MiR-181a-5p also decreased the expression of Ki67, GNAQ, and AKT3, and induced the expression of cleaved-caspase3 in UM tumors. These results suggest that miR-181a-5p inhibits UM development by targeting GNAQ and AKT3.
    Keywords:  AKT3; GNAQ; Uveal melanoma; miR-181a-5p
  44. Biophys J. 2023 Feb 10. pii: S0006-3495(22)02788-6. [Epub ahead of print]122(3S1): 335a-336a
    Probing the role of RNA in prion protein and prion fibril recognition.
    Brian W Paul, Hannah O Brockman, Patricia Soto.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.1872
  45. Cancer Cell Int. 2023 Feb 15. 23(1): 27
    Long non-coding RNA CCL14-AS suppresses invasiveness and lymph node metastasis of colorectal cancer cells by regulating MEP1A.
    Mingzhou Li, Chengmei Huang, Yuanyuan Wu, Lina Zhu, Yaxin Zhang, Yi Zhou, Huali Li, Zhihao Liu, Xinyan Pan, Xin Wang, Junfeng Qiu, Fengtian Li, Wenting Liao.
       BACKGROUND: Long non-coding RNAs (lncRNAs) play important roles in the biology of colorectal cancer (CRC). There are several lncRNAs associated with invasion and metastasis have been characterized in CRC. However, studies focusing on the precise molecular mechanisms by which lncRNAs function in lymph node (LN) metastasis in CRC are still limited.
    METHODS: In this study, by analyzing TCGA dataset, we identified that AC244100.2 (termed CCL14-AS), a novel lncRNA enriched in the cytoplasm, was negatively correlated with LN metastasis and unfavorable prognosis of CRC. In situ hybridization was used to examine CCL14-AS expression in clinical CRC tissues. Various functional experiments including migration assay and wound-healing assay were used to investigate the effects of CCL14-AS on CRC cells migration. The nude mice popliteal lymph node metastasis model assay further confirmed the effects of CCL14-AS in vivo.
    RESULTS: CCL14-AS expression was significantly downregulated in CRC tissues compared to adjacent normal tissues. In addition, low CCL14-AS expression was correlated with advanced T classification, LN metastasis, distant metastasis, and shorter disease-free survival of CRC patients. Functionally, CCL14-AS overexpression inhibited the invasiveness of CRC cells in vitro and LN metastasis in nude mice. On the contrary, knockdown of CCL14-AS promoted the invasiveness and LN metastasis abilities of CRC cells. Mechanistically, CCL14-AS downregulated the expression of MEP1A via interacting with MEP1A mRNA and reduced its stability. Overexpression of MEP1A rescued the invasiveness and LN metastasis abilities in CCL14-AS-overexpressing CRC cells. Moreover, the expression levels of CCL14-AS was negatively correlated with that of MEP1A in CRC tissues.
    CONCLUSIONS: We identified a novel lncRNA, CCL14-AS, as a potential tumor suppressor in CRC. Our findings supported a model in which the CCL14-AS/MEP1A axis serves as critical regulator in CRC progression, suggesting a novel biomarker and therapeutic target in advanced CRC.
    Keywords:  AC244100.2; CCL14-AS; Colorectal cancer; Long noncoding RNA; MEP1A; Metastasis
    DOI:  https://doi.org/10.1186/s12935-023-02866-1
  46. Biophys J. 2023 Feb 10. pii: S0006-3495(22)02059-8. [Epub ahead of print]122(3S1): 186a
    Regulation of LRRK2 dynamics and conformation states by small molecules.
    Jui-Hung Weng.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.1143
  47. Biophys J. 2023 Feb 10. pii: S0006-3495(22)03517-2. [Epub ahead of print]122(3S1): 486a-487a
    In vivo disruption of nuclear HSATII RNA biomolecular condensates.
    Thembalami Dube, Christina A Rabeler, Dawn Carone.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.2601
  48. bioRxiv. 2023 Jan 31. pii: 2023.01.30.526372. [Epub ahead of print]
    Ataxin-2 polyglutamine expansions aberrantly sequester TDP-43, drive ribonucleoprotein condensate transport dysfunction and suppress local translation.
    Denethi Wijegunawardana, Sonali S Vishal, Neha Venkatesh, Pallavi P Gopal.
      Altered RNA metabolism is a common pathogenic mechanism linked to familial and sporadic Amyotrophic lateral sclerosis (ALS). ALS is characterized by mislocalization and aggregation of TDP-43, an RNA-binding protein (RBP) with multiple roles in post-transcriptional RNA processing. Recent studies have identified genetic interactions between TDP-43 and Ataxin-2, a polyglutamine (polyQ) RBP in which intermediate length polyQ expansions confer increased ALS risk. Here, we used live-cell confocal imaging, photobleaching and translation reporter assays to study the localization, transport dynamics and mRNA regulatory functions of TDP-43/Ataxin-2 in rodent primary cortical neurons. We show that Ataxin-2 polyQ expansions aberrantly sequester TDP-43 within ribonucleoprotein (RNP) condensates, and disrupt both its motility along the axon and liquid-like properties. Our data suggest that Ataxin-2 governs motility and translation of neuronal RNP condensates and that Ataxin-2 polyQ expansions fundamentally perturb spatial localization of mRNA and suppress local translation. Overall, these results indicate Ataxin-2 polyQ expansions have detrimental effects on stability, localization, and translation of transcripts critical for axonal and cytoskeletal integrity, particularly important for motor neurons.
    DOI:  https://doi.org/10.1101/2023.01.30.526372
  49. Front Physiol. 2023 ;14 1073625
    Feeding Asian honeybee queens with European honeybee royal jelly alters body color and expression of related coding and non-coding RNAs.
    Amal Abdelmawla, Chen Yang, Xin Li, Mang Li, Chang Long Li, Yi Bo Liu, Xu Jiang He, Zhi Jiang Zeng.
      Background and aims: The Asian honeybee (Apis cerana) and the European honeybee (Apis mellifera) are reproductively isolated. Previous studies reported that exchanging the larval food between the two species, known as nutritional crossbreeding, resulted in obvious changes in morphology, physiology and behavior. This study explored the molecular mechanisms underlying the honeybee nutritional crossbreeding. Methods: This study used full nutritional crossbreeding technology to rear A. cerana queens by feeding them with an A. mellifera royal jelly-based diet in an incubator. The body color and the expression of certain genes, microRNA, lncRNA, and circRNA among nutritional crossbred A. cerana queens (NQ), and control A. cerana queens (CQ) were compared. The biological functions of two target genes, TPH1 and KMO, were verified using RNA interference. Results: Our results showed that the NQ's body color turned yellow compared to the black control queens. Whole transcriptome sequencing results showed that a total of 1484, 311, 92, and 169 DEGs, DElncRNAs, DEmiRNAs, and DEcircRNAs, respectively, were identified in NQ and CQ, in which seven DEGs were enriched for three key pathways (tryptophan, tyrosine, and dopamine) involved in melanin synthesis. Interestingly, eight DElncRNAs and three DEmiRNAs were enriched into the key pathways regulating the above key DEGs. No circRNAs were enriched into these key pathways. Knocking down two key genes (KMO and TPH1) resulted in altered body color, suggesting that feeding NQ's an RNAi-based diet significantly downregulated the expression of TPH1 and KMO in 4-day-old larvae, which confirmed the function of key DEGs in the regulation of honeybee body color. Conclusion: These findings reveal that the larval diets from A. mellifera could change the body color of A. cerana, perhaps by altering the expression of non-coding RNAs and related key genes. This study serves as a model of epigenetic regulation in insect body color induced by environmental factors.
    Keywords:  body color alteration; gene expression; honeybees; non-coding RNA expression; nutritional crossbreed
    DOI:  https://doi.org/10.3389/fphys.2023.1073625
  50. Biophys J. 2023 Feb 10. pii: S0006-3495(22)02894-6. [Epub ahead of print]122(3S1): 357a-358a
    D-RNA selects L-amino acids in a newly characterized aminoacyl-RNA loop ligation.
    Shannon N Kim.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.1978
  51. Annu Rev Anim Biosci. 2023 02 15. 11 57-75
    Extensive Recoding of the Neural Proteome in Cephalopods by RNA Editing.
    Joshua J C Rosenthal, Eli Eisenberg.
      The coleoid cephalopods have the largest brains, and display the most complex behaviors, of all invertebrates. The molecular and cellular mechanisms that underlie these remarkable advancements remain largely unexplored. Early molecular cloning studies of squid ion channel transcripts uncovered an unusually large number of A→I RNA editing sites that recoded codons. Further cloning of other neural transcripts showed a similar pattern. The advent of deep-sequencing technologies and the associated bioinformatics allowed the mapping of RNA editing events across the entire neural transcriptomes of various cephalopods. The results were remarkable: They contained orders of magnitude more recoding editing sites than any other taxon. Although RNA editing sites are abundant in most multicellular metazoans, they rarely recode. In cephalopods, the majority of neural transcripts are recoded. Recent studies have focused on whether these events are adaptive, as well as other noncanonical aspects of cephalopod RNA editing.
    Keywords:  ADAR; RNA editing; adaptation; adenosine deaminase acting on RNA; cephalopods
    DOI:  https://doi.org/10.1146/annurev-animal-060322-114534
  52. Mol Cancer. 2023 Feb 13. 22(1): 30
    Emerging roles of tRNA-derived fragments in cancer.
    Min Fu, Jianmei Gu, Maoye Wang, Jiahui Zhang, Yanke Chen, Pengcheng Jiang, Taofeng Zhu, Xu Zhang.
      tRNA-derived fragments (tRFs) are an emerging category of small non-coding RNAs that are generated from cleavage of mature tRNAs or tRNA precursors. The advance in high-throughput sequencing has contributed to the identification of increasing number of tRFs with critical functions in distinct physiological and pathophysiological processes. tRFs can regulate cell viability, differentiation, and homeostasis through multiple mechanisms and are thus considered as critical regulators of human diseases including cancer. In addition, increasing evidence suggest the extracellular tRFs may be utilized as promising diagnostic and prognostic biomarkers for cancer liquid biopsy. In this review, we focus on the biogenesis, classification and modification of tRFs, and summarize the multifaceted functions of tRFs with an emphasis on the current research status and perspectives of tRFs in cancer.
    Keywords:  Biomarker; Cancer; tRNA halves; tRNA-derived fragments
    DOI:  https://doi.org/10.1186/s12943-023-01739-5
  53. Curr Med Chem. 2023 Feb 14.
    Novel Perspectives for the Diagnosis and Treatment of Gynecological Cancers using Dysregulation of PIWI Protein and PiRNAs as Biomarkers.
    Bahman Yousefi, Fatemeh Sadoughi, Zatollah Asemi, Mohammad Ali Mansournia, Jamal Hallajzadeh.
      The term "gynecological cancer" is used for a group of cancers occurring in the female reproductive system. Some of these cancers are ranked as the leading causes of death in developed and developing countries. The lack of proper diagnostic strategies is one of the most important reasons that make them lethal. PIWI-interacting RNAs or piRNAs are a class of small non-coding RNAs, which contain 24-32 nucleotides. These RNAs take part in some cellular mechanisms, and their role in diverse kinds of cancer is confirmed by accumulative evidence. In this review, we gather some information on the roles of these RNAs and members of the PIWI protein family to provide new insight into accurate diagnostic biomarkers and more effective anti-cancer drugs with fewer side effects.
    Keywords:  PIWI protein; PIWIL2; cervical cancer; ovarian cancer; piRNA
    DOI:  https://doi.org/10.2174/0929867330666230214101837
  54. bioRxiv. 2023 Feb 06. pii: 2023.02.06.527314. [Epub ahead of print]
    Structural basis for inactivation of PRC2 by G-quadruplex RNA.
    Jiarui Song, Anne R Gooding, Wayne O Hemphill, Vignesh Kasinath, Thomas R Cech.
      The histone methyltransferase PRC2 (Polycomb Repressive Complex 2) silences genes via successively attaching three methyl groups to lysine 27 of histone H3. PRC2 associates with numerous pre-mRNA and lncRNA transcripts with a binding preference for G-quadruplex RNA. Here, we present a 3.3Ã…-resolution cryo-EM structure of PRC2 bound to a G-quadruplex RNA. Notably, RNA mediates the dimerization of PRC2 by binding both protomers and inducing a protein interface comprised of two copies of the catalytic subunit EZH2, which limits nucleosome DNA interaction and occludes H3 tail accessibility to the active site. Our results reveal an unexpected mechanism for RNA-mediated inactivation of a chromatin-modifying enzyme. Furthermore, the flexible loop of EZH2 that helps stabilize RNA binding also facilitates the handoff between RNA and DNA, an activity implicated in PRC2 regulation by RNA.
    One-Sentence Summary: Cryo-EM structure of RNA-bound PRC2 dimer elucidates an unexpected mechanism of PRC2 inhibition by RNA.
    DOI:  https://doi.org/10.1101/2023.02.06.527314
  55. Exp Ther Med. 2023 Mar;25(3): 106
    Knockdown of lncRNA SNHG16 attenuates myocardial ischemia‑reoxygenation injury via targeting miR‑183/FOXO1 axis.
    Tao Geng, Zesheng Xu, Jingxian Xing, Yonggang Yuan, Juan Liu.
      Accumulating evidence shows that long non-coding RNAs (lncRNAs) are widely involved in cellular processes of myocardial ischemia/reperfusion (I/R). The present study investigated the functions of lncRNA SNHG16 in myocardial I/R and the mechanism mediated by SNHG16. The myocardial I/R rat and cell model and hypoxia/reoxygenation injury (H/R) models of H9C2 cardiomyocytes were established to detect the expression of SNHG16. Cell Counting Kit-8, flow cytometric and western blot assays were conducted to detect cell viability, apoptosis and protein expression. Myocardial cell apoptosis was assessed by TUNEL staining. Dual-luciferase gene reporter was applied to determine the interaction between the molecules. The expressions of SNHG16 were upregulated in myocardial I/R injury models. Inhibition of SNHG16 relieved myocardial I/R injury in vivo and in vitro silencing of SNHG16 alleviated H/R induced cardiomyocyte apoptosis. To explore the regulatory mechanism, it was discovered that SNHG16 directly interacted with miR-183, while forkhead box O1 (FoxO1) was a target of microRNA (miR)-183. Findings from rescue assays revealed that miR-183 inhibitor and upregulation of FOXO1 can rescue the effect of sh-SNHG16 on H/R-induced cardiomyocyte apoptosis. The results indicated that the lncRNA SNHG16/miR-183/FOXO1 axis exacerbated myocardial cell apoptosis in myocardial I/R injury, suggesting SNHG16 as a potential therapeutic target for myocardial I/R injury.
    Keywords:  forkhead box O1; lncRNA SNHG16; microRNA 183; myocardial ischemia/reperfusion
    DOI:  https://doi.org/10.3892/etm.2023.11805
  56. Lab Invest. 2021 09;pii: S0023-6837(22)00576-1. [Epub ahead of print]101(9): 1142-1152
    LncRNA SNHG15 relieves hyperglycemia-induced endothelial dysfunction via increased ubiquitination of thioredoxin-interacting protein.
    Qian-Qian Zhu, Ming-Chun Lai, Tian-Chi Chen, Xun Wang, Lu Tian, Dong-Lin Li, Zi-Heng Wu, Xiao-Hui Wang, Yun-Yun He, Yang-Yan He, Tao Shang, Yi-Lang Xiang, Hong-Kun Zhang.
      Numerous studies have revealed that hyperglycemia is a pivotal driver of diabetic vascular complications. However, the mechanisms of hyperglycemia-induced endothelial dysfunction in diabetes remain incompletely understood. This study aims to expound on the underlying mechanism of the endothelial dysfunction induced by hyperglycemia from the perspective of long non-coding RNAs (lncRNA). In this study, a downregulation of SNHG15 was observed in the ischemic hind limb of diabetic mice and high glucose (HG)-treated HUVECs. Functionally, the overexpression of SNHG15 promoted cell proliferation, migration, and tube formation, and suppressed cell apoptosis in HG-treated HUVECs. Mechanistically, SNHG15 reduced thioredoxin-interacting protein (TXNIP) expression by enhancing ITCH-mediated ubiquitination of TXNIP. TXNIP overexpression abrogated the protective effect of lncRNA SNHG15 overexpression on HG-induced endothelial dysfunction. The following experiment further confirmed that SNHG15 overexpression promoted angiogenesis of the ischemic hind limb in diabetic mice. In conclusion, SNHG15 is a novel protector for hyperglycemia-induced endothelial dysfunction via decreasing TXNIP expression. Hyperglycemia is a pivotal driver of vascular complications in diabetes. The present study shows that the long non-coding RNA SNHG15 is downregulated under hyperglycemic conditions. Its overexpression improves hyperglycemia-impaired endothelial dysfunction via reduced expression TXNIP, a thioredoxin-interacting protein. As a novel regulator of endothelial function in diabetes, SNHG15 is a potential therapeutic target for diabetic endothelial dysfunction.
    DOI:  https://doi.org/10.1038/s41374-021-00614-5
  57. bioRxiv. 2023 Feb 02. pii: 2023.02.02.526846. [Epub ahead of print]
    Quercetin selectively reduces expanded repeat RNA levels in models of myotonic dystrophy.
    Subodh K Mishra, Sawyer M Hicks, Jesus A Frias, Sweta Vangaveti, Masayuki Nakamori, John D Cleary, Kaalak Reddy, J Andrew Berglund.
      Myotonic dystrophy is a multisystemic neuromuscular disease caused by either a CTG repeat expansion in DMPK (DM1) or a CCTG repeat expansion in CNBP (DM2). Transcription of the expanded alleles produces toxic gain-of-function RNA that sequester the MBNL family of alternative splicing regulators into ribonuclear foci, leading to pathogenic mis-splicing. There are currently no approved treatments that target the root cause of disease which is the production of the toxic expansion RNA molecules. In this study, using our previously established HeLa DM1 repeat selective screening platform, we identified the natural product quercetin as a selective modulator of toxic RNA levels. Quercetin treatment selectively reduced toxic RNA levels and rescued MBNL dependent mis-splicing in DM1 and DM2 patient derived cell lines and in the HSA LR transgenic DM1 mouse model where rescue of myotonia was also observed. Based on our data and its safety profile for use in humans, we have identified quercetin as a priority disease-targeting therapeutic lead for clinical evaluation for the treatment of DM1 and DM2.
    One Sentence Summary: The natural product quercetin reduces toxic RNA in myotonic dystrophy.
    DOI:  https://doi.org/10.1101/2023.02.02.526846
  58. Lab Invest. 2021 Mar;pii: S0023-6837(22)00299-9. [Epub ahead of print]101(3): 341-352
    LncRNA SNHG5 upregulation induced by YY1 contributes to angiogenesis via miR-26b/CTGF/VEGFA axis in acute myelogenous leukemia.
    Zhen-Jiang Li, Jing Cheng, Yuan Song, Hui-Hui Li, Ji-Fu Zheng.
      Acute myelogenous leukemia (AML) is the most common acute leukemia in adults. Despite great progress has been made in this field, the pathogenesis of AML is still not fully understood. We report here the biological role of lncRNA small nucleolar RNA host gene 5 (SNHG5) in the pathogenesis of AML and the underlying mechanisms. The results showed that lncRNA SNHG5 was highly expressed in AML cancer cell lines. In vitro studies displayed that inhibition of SNHG5 with shRNA resulted in suppression of survival, cell cycle progression, migration/invasion of AML and capacity of adhesion and angiogenesis in human umbilical vein endothelial cells. Mechanistic studies revealed a SNHG5/miR-26b/connective tissue growth factor (CTGF)/vascular endothelial growth factor A (VEGFA) axis in the regulation of AML angiogenesis. Finally, Yin Yang 1 (YY1) was found to transactivate and interact with SNHG5 promoter, leading to the upregulation of SNHG5 in AML. Collectively, upregulation of lncRNA SNHG5 mediated by YY1, activates CTGF/VEGFA via targeting miR-26b to regulate angiogenesis of AML. Our work provides new insights into the molecular mechanisms of AML. This study reveals that upregulation of lncRNA small nucleolar RNA host gene 5 (SNHG5), mediated by Yin Yang 1 (YY1), activates connective tissue growth factor (CTGF)/vascular endothelial growth factor (VEGFA) axis via targeting miR-26b to regulate angiogenesis of acute myelogenous leukemia (AML), providing new insights into mechanisms of AML.
    DOI:  https://doi.org/10.1038/s41374-020-00519-9
  59. Cell Rep. 2023 Feb 16. pii: S2211-1247(23)00122-5. [Epub ahead of print]42(2): 112111
    Promiscuous splicing-derived hairpins are dominant substrates of tailing-mediated defense of miRNA biogenesis in mammals.
    Seungjae Lee, David Jee, Sid Srivastava, Acong Yang, Abhinav Ramidi, Renfu Shang, Diane Bortolamiol-Becet, Sébastien Pfeffer, Shuo Gu, Jiayu Wen, Eric C Lai.
      Canonical microRNA (miRNA) hairpins are processed by the RNase III enzymes Drosha and Dicer into ∼22 nt RNAs loaded into an Argonaute (Ago) effector. In addition, splicing generates numerous intronic hairpins that bypass Drosha (mirtrons) to yield mature miRNAs. Here, we identify hundreds of previously unannotated, splicing-derived hairpins in intermediate-length (∼50-100 nt) but not small (20-30 nt) RNA data. Since we originally defined mirtrons from small RNA duplexes, we term this larger set as structured splicing-derived RNAs (ssdRNAs). These associate with Dicer and/or Ago complexes, but generally accumulate modestly and are poorly conserved. We propose they contaminate the canonical miRNA pathway, which consequently requires defense against the siege of splicing-derived substrates. Accordingly, ssdRNAs/mirtrons comprise dominant hairpin substrates for 3' tailing by multiple terminal nucleotidyltransferases, notably TUT4/7 and TENT2. Overall, the rampant proliferation of young mammalian mirtrons/ssdRNAs, coupled with an inhibitory molecular defense, comprises a Red Queen's race of intragenomic conflict.
    Keywords:  CP: Molecular biology; TENT enzyme; TUTase; intragenomic conflict; microRNA; mirtron; ssdRNA; structured splicing-derived RNA
    DOI:  https://doi.org/10.1016/j.celrep.2023.112111
  60. Biophys J. 2023 Feb 15. pii: S0006-3495(23)00105-4. [Epub ahead of print]
    The Effects of RNA.DNA-DNA Triple Helices on Nucleosome Structures and Dynamics.
    Havva Kohestani, Jeff Wereszczynski.
      Non-coding RNAs (ncRNAs) are an emerging epigenetic factor and have been recognized as playing a key role in many gene expression pathways. Structurally, binding of ncRNAs to isolated DNA is strongly dependent on sequence complementary, and results in the formation of an RNA.DNA-DNA (RDD) triple helix. However, in vivo DNA is not isolated, but is packed in chromatin fibers, the fundamental unit of which is the nucleosome. Biochemical experiments have shown that ncRNA binding to nucleosomal DNA is elevated at DNA entry and exit sites and is dependent on the presence of the H3 N-terminal tails. However, the structural and dynamical bases for these mechanisms remains unknown. Here, we have examined the mechanisms and effects of RDD formation in the context of the nucleosome using a series of all-atom molecular dynamics simulations. Results highlight the importance of DNA sequence on complex stability, elucidate the effects of the H3 tails on RDD structures, show how RDD formation impacts the structure and dynamics of the H3 tails, and show how RNA alters the local and global DNA double helical structure. Together, our results suggest ncRNAs can modify nucleosome, and potentially higher-order chromatin, structures and dynamics as a means of exerting epigenetic control.
    DOI:  https://doi.org/10.1016/j.bpj.2023.02.013
  61. Phage (New Rochelle). 2022 Sep 01. 3(3): 136-140
    RNA Management During T7 Infection.
    Aline Tabib-Salazar, Sivaramesh Wigneshweraraj.
      Post-transcriptional regulation (PTR) determines the fate of RNA in the cell and represents an important control point in the flow of genetic information and thus underpins many, if not all, aspects of cell function. Host takeover by phages through misappropriation of the bacterial transcription machinery is a relatively advanced area of research. However, several phages encode small regulatory RNAs, which are major mediators of PTR, and produce specific proteins to manipulate bacterial enzymes involved in RNA degradation.1-4 However, PTR during phage development still represents an understudied area of phage-bacteria interaction biology. In this study, we discuss the potential role PTR could play in determining the fate of RNA during the lifecycle of the prototypic phage T7 in Escherichia coli.
    Keywords:  Hfq; RNA; RNA polymerase; T7 phage; post-transcriptional regulation; transcription
    DOI:  https://doi.org/10.1089/phage.2022.0029
  62. Biophys J. 2023 Feb 10. pii: S0006-3495(22)02591-7. [Epub ahead of print]122(3S1): 296a
    Structure and dynamics of RNA in biomolecular condensate.
    Hung T Nguyen, D Thirumalai.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.1675
  63. J Cell Biol. 2023 Apr 03. pii: e202209115. [Epub ahead of print]222(4):
    Quality control ensures fidelity in ribosome assembly and cellular health.
    Melissa D Parker, Katrin Karbstein.
      The coordinated integration of ribosomal RNA and protein into two functional ribosomal subunits is safeguarded by quality control checkpoints that ensure ribosomes are correctly assembled and functional before they engage in translation. Quality control is critical in maintaining the integrity of ribosomes and necessary to support healthy cell growth and prevent diseases associated with mistakes in ribosome assembly. Its importance is demonstrated by the finding that bypassing quality control leads to misassembled, malfunctioning ribosomes with altered translation fidelity, which change gene expression and disrupt protein homeostasis. In this review, we outline our understanding of quality control within ribosome synthesis and how failure to enforce quality control contributes to human disease. We first provide a definition of quality control to guide our investigation, briefly present the main assembly steps, and then examine stages of assembly that test ribosome function, establish a pass-fail system to evaluate these functions, and contribute to altered ribosome performance when bypassed, and are thus considered "quality control."
    DOI:  https://doi.org/10.1083/jcb.202209115
  64. Elife. 2023 Feb 15. pii: e83853. [Epub ahead of print]12
    A comprehensive survey of C. elegans argonaute proteins reveals organism-wide gene regulatory networks and functions.
    Uri Seroussi, Andrew Lugowski, Lina Wadi, Robert X Lao, Alexandra R Willis, Winnie Zhao, Adam E Sundby, Amanda G Charlesworth, Aaron W Reinke, Julie M Claycomb.
      Argonaute (AGO) proteins associate with small RNAs to direct their effector function on complementary transcripts. The nematode C. elegans contains an expanded family of 19 functional AGO proteins, many of which have not been fully characterized. In this work we systematically analyzed every C. elegans AGO, using CRISPR-Cas9 genome editing to introduce GFP::3xFLAG tags. We have characterized the expression patterns of each AGO throughout development, identified small RNA binding complements, and determined the effects of ago loss on small RNA populations and developmental phenotypes. Our analysis indicates stratification of subsets of AGOs into distinct regulatory modules, and integration of our data led us to uncover novel stress-induced fertility and pathogen response phenotypes due to ago loss.
    Keywords:  C. elegans; developmental biology; genetics; genomics
    DOI:  https://doi.org/10.7554/eLife.83853
  65. Nat Commun. 2023 Feb 15. 14(1): 842
    Chemoproteomic discovery of a human RNA ligase.
    Yizhi Yuan, Florian M Stumpf, Lisa A Schlor, Olivia P Schmidt, Philip Saumer, Luisa B Huber, Matthias Frese, Eva Höllmüller, Martin Scheffner, Florian Stengel, Kay Diederichs, Andreas Marx.
      RNA ligases are present across all forms of life. While enzymatic RNA ligation between 5'-PO4 and 3'-OH termini is prevalent in viruses, fungi, and plants, such RNA ligases are yet to be identified in vertebrates. Here, using a nucleotide-based chemical probe targeting human AMPylated proteome, we have enriched and identified the hitherto uncharacterised human protein chromosome 12 open reading frame 29 (C12orf29) as a human enzyme promoting RNA ligation between 5'-PO4 and 3'-OH termini. C12orf29 catalyses ATP-dependent RNA ligation via a three-step mechanism, involving tandem auto- and RNA AMPylation. Knock-out of C12ORF29 gene impedes the cellular resilience to oxidative stress featuring concurrent RNA degradation, which suggests a role of C12orf29 in maintaining RNA integrity. These data provide the groundwork for establishing a human RNA repair pathway.
    DOI:  https://doi.org/10.1038/s41467-023-36451-x
  66. Front Genet. 2023 ;14 1141282
    Corrigendum: Role of non-coding RNA in the pathophysiology and treatment of intrauterine adhesion.
    Hui-Dong Liu, Shao-Wei Wang.
      [This corrects the article DOI: 10.3389/fgene.2022.948628.].
    Keywords:  exosome; intrauterine adhesion; mesenchymal stem cells; microRNA; non-coding-RNA
    DOI:  https://doi.org/10.3389/fgene.2023.1141282
  67. Res Sq. 2023 Feb 08. pii: rs.3.rs-2440278. [Epub ahead of print]
    Dynamical control enables the formation of demixed biomolecular condensates.
    Rohit Pappu, Andrew Lin, Kiersten Ruff, Ameya Jalihal, Furqan Dar, Matthew King, Jared Lalmansingh, Ammon Posey, Ian Seim, Amy Gladfelter.
      Macromolecular phase separation underlies the regulated formation and dissolution of biomolecular condensates. What is unclear is how condensates of distinct and shared macromolecular compositions form and coexist within cellular milieus. Here, we use theory and computation to establish thermodynamic criteria that must be satisfied to achieve compositionally distinct condensates. We applied these criteria to an archetypal ribonucleoprotein condensate and discovered that demixing into distinct protein-RNA condensates cannot be the result of purely thermodynamic considerations. Instead, demixed, compositionally distinct condensates arise due to asynchronies in timescales that emerge from differences in long-lived protein-RNA and RNA-RNA crosslinks. This type of dynamical control is also found to be active in live cells whereby asynchronous production of molecules is required for realizing demixed protein-RNA condensates. We find that interactions that exert dynamical control provide a versatile and generalizable way to influence the compositions of coexisting condensates in live cells.
    DOI:  https://doi.org/10.21203/rs.3.rs-2440278/v1
  68. Biophys J. 2023 Feb 10. pii: S0006-3495(22)01284-X. [Epub ahead of print]122(3S1): 27a
    RNA excited states by NMR and their impact on function.
    Katja Petzold.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.368
  69. Neurol Sci. 2023 Feb 13.
    The regulatory function of lncRNA and constructed network in epilepsy.
    Suhui Kuang, Jiaqi Wang, Zhirong Wei, Feng Zhai, Shuli Liang.
       BACKGROUND: Epilepsy is a neurological disease characterized by neural network dysfunction. Although most reports indicate that the pathological process of epilepsy is related to inflammation, synaptic plasticity, cell apoptosis, and ion channel dysfunction, the underlying molecular mechanisms of epilepsy are not fully understood.
    METHODS: This review summarizes the latest literature on the roles and characteristics of long noncoding RNAs (lncRNAs) in the pathogenesis of epilepsy.
    RESULTS: lncRNAs are a class of long transcripts without protein-coding functions that perform important regulatory functions in various biological processes. lncRNAs are involved in the regulation of the pathological process of epilepsy and are abnormally expressed in both patients and animal models. This review provides an overview of research progress in epilepsy, the multifunctional features of lncRNAs, the lncRNA expression pattern related to epileptogenesis and status epilepticus, and the potential mechanisms for the two interactions contributing to epileptogenesis and progression.
    CONCLUSION: lncRNAs can serve as new diagnostic markers and therapeutic targets for epilepsy in the future.
    Keywords:  Constructed network; Epilepsy; Pathways; lncRNA; miRNA
    DOI:  https://doi.org/10.1007/s10072-023-06648-5
  70. Mol Biol Rep. 2023 Feb 14.
    LncRNA PCAT6 promotes proliferation, migration, invasion, and epithelial-mesenchymal transition of lung adenocarcinoma cell by targeting miR-545-3p.
    Chuyi Yang, Hongyu Huang, Yongpeng Li, Ting Zhuo, Lu Zhu, Chenyang Luo, Yanbin Wu, Shouming Qin.
       BACKGROUND: Lung cancer is a high incidence cancer on a worldwide basis and has become a major public health problem. Lung adenocarcinoma (LUAD) makes up approximately half of all lung cancers and is a threat to human health. Long non-coding RNAs (lncRNAs) is an important regulator of the development and progression of lung adenocarcinoma. In this manuscript we examined the role and potential mechanism of lncRNA PCAT6 in the development of LUAD.
    METHODS AND RESULTS: Differences in lncRNA PCAT6 levels between LUAD samples and normal samples were first explored in the GEPIA database. We found that lncRNA PCAT6 expression was elevated, which was also validated in lung adenocarcinoma tissues and cell lines. Using western blotting, CCK-8, EdU, wound healing and transwell assays, we found that knockdown of lncRNA PCAT6 inhibited EMT, proliferation, migration, and invasion of LUAD cells. We noted a predicted a binding site for lncRNA PCAT6 and miR-545-3p through conducting bioinformatic analyses, and their binding was subsequently verified by a dual-luciferase reporter assay. Rescue experiments confirmed that miR-545-3p inhibitor partially abolished the inhibition function of lncRNA PCAT6 knockdown on LUAD cells. In addition, we predicted the downstream target genes of miR-545-3p and verified them by RT-qPCR. We found that EGFR was reduced in the silence of lncRNA PCAT6 and upregulated after miR-545-3p inhibition.
    CONCLUSION: This study demonstrates that lncRNA PCAT6 promotes a more aggressive LUAD phenotype by sponging miR-545-3p. This finding may provide new ideas for the treatment of lung cancer.
    Keywords:  EMT; Lung adenocarcinoma; lncRNA PCAT6; miR-545- 3p
    DOI:  https://doi.org/10.1007/s11033-023-08259-x
  71. BMC Genom Data. 2023 Feb 14. 24(1): 4
    Role of cytoskeleton-related proteins in the acrosome reaction of Eriocheir sinensis spermatozoa.
    Yulian Tang, Lishuang Sun, Shu Li, Huiting Liu, Lvjing Luo, Zhengyu Chen, Genliang Li.
      Cytoskeleton-related proteins are essential for cell shape maintenance and cytoskeleton remodeling. The spermatozoa of Eriocheir sinensis (Chinese mitten crab) have a unique cellular structure, and the mechanism of spermatozoal metamorphosis during the acrosome reaction is not well understood. In this study, the E. sinensis spermatozoa were induced using calcium ionophore A23187 to undergo the acrosome reaction in vitro, and the acrosome-reacting and fresh (non-reacting) spermatozoa were collected separately. The differential expression of cytoskeleton-related protein genes in acrosome-reacting and fresh spermatozoa of E. sinensis was analyzed by whole transcriptome sequencing and bioinformatics analysis, and PPI network and miRNA-mRNA regulation network were constructed to analyze their possible function and regulation mechanism. The results showed that numerous differentially expressed cytoskeleton-related protein genes, miRNAs and lncRNAs were found in acrosome-reacting and fresh spermatozoa of E. sinensis; 27 cytoskeleton-related protein genes were down regulated and 687 miRNAs were up regulated in acrosome-reacting spermatozoa; 147 miRNAs target these 27 cytoskeleton-related protein genes. In the PPI networks, RAC1, BCAR1, RDX, NCKAP1, EPS8, CDC42BPA, LIMK1, ELMO2, GNAI1 and OCRL were identified as hub proteins. These proteins are mainly involved in the regulation of cytoskeleton organization, actin cytoskeleton organization, microtubule skeleton organization and small GTPase-mediated signal transduction and other biological processes, and play roles in pathways such as actin cytoskeletal regulation and axon guidance. miR-9, miR-31 and two novel miRNAs in the miRNA-mRNA regulatory network are the core miRNAs targeting cytoskeleton-related protein genes. miR-9 targets and regulates OBSCN, CDC42BPA, ELMO2, BCAS3, TPR and OCRL; while miR-31 targets and regulates CDC42BPA and TPR. This study provides a theoretical basis for revealing the mechanism of acrosome reaction under the special spermatozoa morphology of E. sinensis.
    Keywords:  Acrosome reaction; Cytoskeleton-related protein; Eriocheir sinensis; Spermatozoa; miRNA
    DOI:  https://doi.org/10.1186/s12863-023-01112-x
  72. bioRxiv. 2023 Jan 31. pii: 2023.01.29.526143. [Epub ahead of print]
    PerturbSci-Kinetics : Dissecting key regulators of transcriptome kinetics through scalable single-cell RNA profiling of pooled CRISPR screens.
    Zihan Xu, Andras Sziraki, Jasper Lee, Wei Zhou, Junyue Cao.
      Here we described PerturbSci-Kinetics , a novel combinatorial indexing method for capturing three-layer single-cell readout ( i . e ., whole transcriptome, nascent transcriptome, sgRNA identities) across hundreds of genetic perturbations. Through PerturbSci-Kinetics profiling of pooled CRISPR screens targeting a variety of biological processes, we were able to decipher the complexity of RNA regulations at multiple levels ( e . g ., synthesis, processing, degradation), and revealed key regulators involved in miRNA and mitochondrial RNA processing pathways. Our technique opens up the possibility of systematically decoding the genome-wide regulatory network underlying RNA temporal dynamics at scale and cost-effectively.
    DOI:  https://doi.org/10.1101/2023.01.29.526143
  73. Front Plant Sci. 2023 ;14 1093913
    Genome-wide characterization of the PP2C gene family in peanut (Arachis hypogaea L.) and the identification of candidate genes involved in salinity-stress response.
    Zhanwei Wu, Lu Luo, Yongshan Wan, Fengzhen Liu.
      Plant protein phosphatase 2C (PP2C) play important roles in response to salt stress by influencing metabolic processes, hormone levels, growth factors, etc. Members of the PP2C family have been identified in many plant species. However, they are rarely reported in peanut. In this study, 178 PP2C genes were identified in peanut, which were unevenly distributed across the 20 chromosomes, with segmental duplication in 78 gene pairs. AhPP2Cs could be divided into 10 clades (A-J) by phylogenetic analysis. AhPP2Cs had experienced segmental duplications and strong purifying selection pressure. 22 miRNAs from 14 different families were identified, targeting 57 AhPP2C genes. Gene structures and motifs analysis exhibited PP2Cs in subclades AI and AII had high structural and functional similarities. Phosphorylation sites of AhPP2C45/59/134/150/35/121 were predicted in motifs 2 and 4, which located within the catalytic site at the C-terminus. We discovered multiple MYB binding factors and ABA response elements in the promoter regions of the six genes (AhPP2C45/59/134/150/35/121) by cis-elements analysis. GO and KEGG enrichment analysis confirmed AhPP2C-A genes in protein binding, signal transduction, protein modification process response to abiotic stimulus through environmental information processing. Based on RNA-Seq data of 22 peanut tissues, clade A AhPP2Cs showed a varying degree of tissue specificity, of which, AhPP2C35 and AhPP2C121 specifically expressed in seeds, while AhPP2C45/59/134/150 expressed in leaves and roots. qRT-PCR indicated that AhPP2C45 and AhPP2C134 displayed significantly up-regulated expression in response to salt stress. These results indicated that AhPP2C45 and AhPP2C134 could be candidate PP2Cs conferring salt tolerance. These results provide further insights into the peanut PP2C gene family and indicate PP2Cs potentially involved in the response to salt stress, which can now be further investigated in peanut breeding efforts to obtain cultivars with improved salt tolerance.
    Keywords:  PP2C gene family; gene expression analysis; genome-wide identification; peanut; salt stress
    DOI:  https://doi.org/10.3389/fpls.2023.1093913
  74. Protein Sci. 2023 Feb 13. e4594
    PrePCI: A structure- and chemical similarity-informed database of predicted protein compound interactions.
    Stephen J Trudeau, Howook Hwang, Deepika Mathur, Kamrun Begum, Donald Petrey, Diana Murray, Barry Honig.
      We describe the Predicting Protein Compound Interactions (PrePCI) database which comprises over 5 billion predicted interactions between nearly 7 million chemical compounds and 19,797 human proteins. PrePCI relies on a proteome-wide database of structural models based on both traditional modeling techniques and the AlphaFold Protein Structure Database. Sequence and structural similarity-based metrics are established between template proteins, T, in the Protein Data Bank that bind compounds, C, and query proteins in the model database, Q. When these metrics pass a sequence threshold value, it is assumed that C also binds to Q with a likelihood ratio derived from machine learning. If the relationship is based on structure, this LR is based on a scoring function that measures the extent to which C is compatible with the binding site of Q as described in the LT-scanner algorithm. For every predicted complex derived in this way, chemical similarity based on the Tanimoto coefficient identifies other small molecules that may bind to Q. A likelihood ratio for the binding of C to Q is obtained from Naïve Bayesian statistics. The PrePCI database can be queried by entering a UniProt ID or gene name for a protein to obtain a list of compounds predicted to bind to it along with associated LRs. Alternatively, entering an identifier for the compound outputs a list of proteins it is predicted to bind. Specific applications of the database to lead discovery, drug mechanism of action elucidation and biological function annotation are described. This article is protected by copyright. All rights reserved.
    Keywords:  Protein compound interactions; chemical similarity; protein-compound database; structural alignment
    DOI:  https://doi.org/10.1002/pro.4594
  75. J Med Virol. 2023 Feb 17.
    Rationally Designed Synthetic Vectors for Therapeutic Nucleic Acid Delivery against Human Cytomegalovirus Infection.
    Xuemei Ge, Dabbu Kumar Jaijyan, Wei Wang, Tong Cheng, Qiyi Tang, Fei Wu, Tuo Jin, Hua Zhu.
      RNA therapy represents a great way to precisely regulate cellular processes by modulating the gene expression. Despite this potential, a profound gap exists in our knowledge of how to subsequently deliver these RNAs into the specific target cells and turn therapeutically active RNAs into practical medicines. An advanced series of interlocked, thermodynamically self-regulated processes that enable the precise assembly of functional synthetic carriers of siRNA to the target cells in vivo was developed. To demonstrate the efficacy of this delivery system, we used it to treat human cytomegalovirus (HCMV) infection in a humanized mouse model. In this study, we use small interfering RNA (siRNA) and small complementary RNA (scRNA) to inhibit the expressions of two HCMV genes, IE1 and IE2. The auto-regulated nanocarrier polywraplex with core-shell structure was designed to condense and package these RNAs for delivering. To allow these particles recognize the HCMV-infected cells, a ligand was coupled on the surface of nanoparticle, which would specifically target the HCMV-encoded CX3 CL1 chemokine receptor presented in the HCMV-infected cells. The results demonstrated that the polywraplex conjugated with the target molecule CX3 CL1 effectively and specifically delivered the siRNA/scRNA to HCMV infected cells and inhibited virus growth in vitro and in vivo. This article is protected by copyright. All rights reserved.
    Keywords:  chemokine; human cytomegalovirus infection; nanoparticle; surface-assembly; synthetic carrier of nucleic acid
    DOI:  https://doi.org/10.1002/jmv.28586
  76. bioRxiv. 2023 Feb 08. pii: 2023.02.08.527468. [Epub ahead of print]
    Inverse-folding design of yeast telomerase RNA increases activity in vitro.
    Kevin J Lebo, David C Zappulla.
      Saccharomyces cerevisiae telomerase RNA, TLC1, is an 1157 nt non-coding RNA that functions as both a template for DNA synthesis and a flexible scaffold for telomerase RNP holoenzyme protein subunits. The tractable budding yeast system has provided landmark discoveries about telomere biology in vivo , but yeast telomerase research has been hampered by the fact that the large TLC1 RNA subunit does not support robust telomerase activity in vitro . In contrast, 155-500 nt miniaturized TLC1 alleles comprising the catalytic core domain and lacking the RNA's long arms do reconstitute robust activity. We hypothesized that full-length TLC1 is prone to misfolding in vitro . To create a full-length yeast telomerase RNA predicted to fold into its biological relevant structure, we took an inverse RNA folding approach, changing 59 nucleotides predicted to increase the energetic favorability of folding into the modeled native structure based on the p-num feature of Mfold software. The sequence changes lowered the predicted ∆G in this "determined-arm" allele, DA-TLC1, by 61 kcal/mol (-19%) compared to wild type. We tested DA-TLC1 for reconstituted activity and found it to be ∼5-fold more robust than wild-type TLC1, suggesting that the inverse-folding design indeed improved folding in vitro into a catalytically active conformation. We also tested if DA-TLC1 functions in vivo and found that it complements a tlc1 ∆ strain, allowing cells to avoid senescence and maintain telomeres of nearly wild-type length. However, all inverse-designed RNAs that we tested had reduced abundance in vivo . In particular, inverse-designing nearly all of the Ku arm caused a profound reduction in telomerase RNA abundance in the cell and very short telomeres. Overall, these results show that inverse design of S. cerevisiae telomerase RNA increases activity in vitro , while reducing abundance in vivo . This study provides a biochemically and biologically tested approach to inverse-design RNAs using Mfold that could be useful for controlling RNA structure in basic research and biomedicine.
    DOI:  https://doi.org/10.1101/2023.02.08.527468
  77. J Obstet Gynaecol. 2023 Dec;43(1): 2174836
    Evaluation of long noncoding RNA (LncRNA) in pathogenesis of HELLP syndrome: diagnostic and future approach.
    Shahrzad Amirlatifi, Zahra Kooshari, Kiana Salmani, Maryam Fallah Ziyarani, Sepideh Azizi, Elena Ghotbi, Bita Zolali.
      HELLP syndrome is a disorder during pregnancy which is defined by elevation of liver enzymes, haemolysis, and low platelet count. This syndrome is a multifactorial one and both genetic and environmental components can have a crucial role in this syndrome's pathogenesis. Long noncoding RNAs (lncRNAs), are defined as long non-protein coding molecules (more than 200 nucleotides), which are functional units in most cellular processes such as cell cycle, differentiation, metabolism and some diseases progression. As these markers discovered, there has been some evidence that they have an important role in the function of some organs, such as placenta; therefore, alteration and dysregulation of these RNAs can develop or alleviate HELLP disorder. Although the role of lncRNAs has been shown in HELLP syndrome, the process is still unclear. In this review, our purpose is to evaluate the association between molecular mechanisms of lncRNAs and HELLP syndrome pathogenicity to elicit some novel approaches for HELLP diagnosis and treatment.
    Keywords:  HELLP syndrome; LncRNA; diagnostic; molecular pathway; pathogenesis; signaling
    DOI:  https://doi.org/10.1080/01443615.2023.2174836
  78. Crit Rev Toxicol. 2023 Feb 15. 1-33
    Regulatory roles of non-coding RNAs and m6A modification in trophoblast functions and the occurrence of its related adverse pregnancy outcomes.
    Wang Rong, Wan Shukun, Wang Xiaoqing, Huang Wenxin, Dai Mengyuan, Mi Chenyang, Huidong Zhang.
      Adverse pregnancy outcomes, such as preeclampsia, gestational diabetes mellitus, fetal growth restriction, and recurrent miscarriage, occur frequently in pregnant women and might further induce morbidity and mortality for both mother and fetus. Increasing studies have shown that dysfunctions of human trophoblast are related to these adverse pregnancy outcomes. Recent studies also showed that environmental toxicants could induce trophoblast dysfunctions. Moreover, non-coding RNAs (ncRNAs) have been reported to play important regulatory roles in various cellular processes. However, the roles of ncRNAs in the regulation of trophoblast dysfunctions and the occurrence of adverse pregnancy outcomes still need to be further investigated, especially with exposure to environmental toxicants. In this review, we analyzed the regulatory mechanisms of ncRNAs and m6A methylation modification in the dysfunctions of trophoblast cells and the occurrence of adverse pregnancy outcomes and also summarized the harmful effects of environmental toxicants. In addition to DNA replication, mRNA transcription, and protein translation, ncRNAs and m6A modification might be considered as the fourth and fifth elements that regulate the genetic central dogma, respectively. Environmental toxicants might also affect these processes. In this review, we expect to provide a deeper scientific understanding of the occurrence of adverse pregnancy outcomes and to discover potential biomarkers for the diagnosis and treatment of these outcomes.
    Keywords:  adverse pregnancy outcomes; environmental toxicants; m6A; ncRNAs; trophoblast dysfunctions
    DOI:  https://doi.org/10.1080/10408444.2022.2144711
  79. Res Sq. 2023 Feb 10. pii: rs.3.rs-2507391. [Epub ahead of print]
    Environmentally Induced Sperm RNAs Transmit Cancer Susceptibility to Offspring in a Mouse Model.
    Raquel da Cruz, Odalys Dominguez, Elaine Chen, Alexandra Gonsiewski, Apsra Nasir, M Idalia Cruz, Xiaojun Zou, Susana Galli, Kepher Makambi, Matthew McCoy, Marcel Schmidt, Lu Jin, Ivana Peran, Sonia de Assis.
      DNA sequence accounts for the majority of disease heritability, including cancer. Yet, not all familial cancer cases can be explained by genetic factors. It is becoming clear that environmentally induced epigenetic inheritance occurs and that the progeny's traits can be shaped by parental environmental experiences. In humans, epidemiological studies have implicated environmental toxicants, such as the pesticide DDT, in intergenerational cancer development, including breast and childhood tumors. Here, we show that the female progeny of males exposed to DDT in the pre-conception period have higher susceptibility to developing aggressive tumors in mouse models of breast cancer. Sperm of DDT-exposed males exhibited distinct patterns of small non-coding RNAs, with an increase in miRNAs and a specific surge in miRNA-10b levels. Remarkably, embryonic injection of the entire sperm RNA load of DDT-exposed males, or synthetic miRNA-10b, recapitulated the tumor phenotypes observed in DDT offspring. Mechanistically, miR-10b injection altered the transcriptional profile in early embryos with enrichment of genes associated with cell differentiation, tissue and immune system development. In adult DDT-derived progeny, transcriptional and protein analysis of mammary tumors revealed alterations in stromal and in immune system compartments. Our findings reveal a causal role for sperm RNAs in environmentally induced inheritance of cancer predisposition and, if confirmed in humans, this could help partially explain some of the "missing heritability" of breast, and other, malignancies.
    DOI:  https://doi.org/10.21203/rs.3.rs-2507391/v1
  80. Int J Rheum Dis. 2023 Feb 15.
    Long non-coding RNA telomerase RNA elements improve glucocorticoid-induced osteoporosis by EZH2 to regulate DKK1.
    He Hu, Xiaodong Guo, Tingting Mu, Huifang Song.
       BACKGROUND: Glucocorticoid-induced osteoporosis is the most common secondary cause of osteoporosis, which increases the risk of fracture. Long non-coding RNA telomerase RNA elements (TERC) has been proven to be closely related to osteoporosis. However, the role of TERC in glucocorticoid-induced osteoporosis and its underlying molecular mechanism remains unclear.
    METHODS: The in vitro model of osteoporosis was established after bone marrow mesenchymal stem cells (BMSCs) were exposed to dexamethasone (DEX). The cell viability, alkaline phosphatase (ALP) activity and mineralized nodules of BMSCs were evaluated. The messenger RNA and protein levels were detected by quantitative real-time polymerase chain reaction and Western blot. The interaction between TERC, enhancer of zeste homolog 2 (EZH2) and dickkopf-1 (DKK1) was confirmed by chromatin immunoprecipitation and RNA immunoprecipitation assays.
    RESULTS: Bone marrow mesenchymal stem cells were isolated, identified and induced osteogenic differentiation. The findings showed that the levels of osteogenic marker genes, including ALP, Runt-related transcription factor 2 (RUNX2) and osteocalcin (OCN) in BMSCs were increased dependent on the osteogenic induction time. Similarly, TERC was significantly increased, but DKK1 was significantly decreased during BMSC osteogenic differentiation. Functional research showed that TERC overexpression promoted cell viability, ALP activity and mineralized nodules of BMSCs and increased the levels of osteogenic differentiation-related genes (ALP, RUNX2 and OCN), and TERC overexpression increased EZH2 protein level. Moreover, the decrease of cell viability, ALP activity and mineralized nodules induced by DEX was reversed by TERC overexpression. Furthermore, TERC inhibited DKK1 expression by promoting the histone modification of DKK1, and TERC overexpression alleviated DEX suppressed osteogenic differentiation of BMSCs by interaction with EZH2 to regulate DKK1.
    CONCLUSION: Our findings illustrated that TERC overexpression alleviated DEX-induced osteoporosis by recruiting EZH2 to regulate DKK1. Our research provided a novel direction for the treatment of glucocorticoid-induced osteoporosis.
    Keywords:  DKK1; EZH2; glucocorticoid-induced osteoporosis; lncRNA TERC
    DOI:  https://doi.org/10.1111/1756-185X.14567
  81. Biophys J. 2023 Feb 10. pii: S0006-3495(22)02531-0. [Epub ahead of print]122(3S1): 284a
    Towards a unified pipeline for tissue-scale localization and identification of individual RNA molecules.
    Alex E Rojewski, Max Schweiger, Sina Jazani, Douglas P Shepherd, Steve Pressé.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.1615
  82. Biomed Res Int. 2023 ;2023 5403344
    Long Noncoding RNA LINC01503 Silencing Suppresses KLK4 Expression to Impede Pancreatic Cancer Development as miR-1321 Sponge.
    Baiping An, Yi Cai, Jie Zhu, Yuan Liu.
       Background: Long intergenic nonprotein coding RNA 1503 (LINC01503) was reportedly oncogenic in several malignancies, whereas whether it contributed to pancreatic cancer tumorigenesis and progression requires to be verified.
    Methods: The expression pattern of LINC01503 was monitored via qRT-PCR assay in normal cells and cancerous pancreatic cancer cells. The introduction of silencing LINC01503 was to verify the relation between LINC01503 expression and cell growth. Then, the targeting relationship of LINC01503 to miR-1321 was confirmed by bioinformatics predication and luciferase reporter assay. In addition, luciferase reporter assays evaluated the binding of miR-1321 to the 3'-untranslated region of KLK4. Overexpressing KLK4 and inhibiting LINC01503 was introduced in tumor cells to investigate the corresponding impacts on pancreatic cancer cell proliferation and migration.
    Results: LINC01503 and KLK4 were highly abundant in pancreatic cancer cells. Mechanistically, miR-1321 bound to LINC01503 and KLK4. Downregulating LINC01503 promoted the availability of miR-1321 in pancreatic cancer cells and thus repressed KLK4 expression. KLK4 overexpression abolished the impediment of LINC01503 depletion on cell proliferation and migration.
    Conclusion: Oncogenic function of LINC01503 was dependent on KLK4 upregulation by sponging miR-1321. Revealing the tumor-promoting property of LINC01503 in pancreatic cancer may confer new biomarkers for this malignancy.
    DOI:  https://doi.org/10.1155/2023/5403344
  83. Curr Osteoporos Rep. 2023 Feb 16.
    Copy Number Variation and Osteoporosis.
    Nika Lovšin.
       PURPOSE OF REVIEW: The purpose of this review is to summarize recent findings on copy number variations and susceptibility to osteoporosis.
    RECENT FINDINGS: Osteoporosis is highly influenced by genetic factors, including copy number variations (CNVs). The development and accessibility of whole genome sequencing methods has accelerated the study of CNVs and osteoporosis. Recent findings include mutations in novel genes and validation of previously known pathogenic CNVs in monogenic skeletal diseases. Identification of CNVs in genes previously associated with osteoporosis (e.g. RUNX2, COL1A2, and PLS3) has confirmed their importance in bone remodelling. This process has been associated also with the ETV1-DGKB, AGBL2, ATM, and GPR68 genes, identified by comparative genomic hybridisation microarray studies. Importantly, studies in patients with bone pathologies have associated bone disease with the long non-coding RNA LINC01260 and enhancer sequences residing in the HDAC9 gene. Further functional investigation of genetic loci harbouring CNVs associated with skeletal phenotypes will reveal their role as molecular drivers of osteoporosis.
    Keywords:  Bone mineral density; Copy number variation; Fragility fractures; Osteoporosis; Structural variations
    DOI:  https://doi.org/10.1007/s11914-023-00773-y
  84. Biophys J. 2023 Feb 10. pii: S0006-3495(22)03300-8. [Epub ahead of print]122(3S1): 441a
    Direct observation of RNA structure and dynamics in repeat-RNA assemblies using single molecule fluorescence microscopy.
    Roumita Moulick, Margaret L Rodgers, Sarah A Woodson.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.2384
  85. Front Endocrinol (Lausanne). 2023 ;14 1120216
    A novel pyroptosis gene expression-based risk score for survival in gastric cancer.
    Jiali Hu, Yang Song, Xintian Cai, Halike Halina, Kun Qiao, Jiajie Lu, Chengliang Yin, Feng Gao.
       Background: Gastric cancer (GC) is a highly heterogeneous disease, which makes treatment and prognosis prediction difficult. Pyroptosis plays a vital role in the development of GC and influence the prognosis of GC. Long non-coding RNAs (lncRNAs), as regulators of gene expressions, are among putative biomarkers and therapeutic targets. However, the importance of pyroptosis-associated lncRNAs is still unclear in predicting prognosis in gastric cancer.
    Methods: In this study, the mRNA expression profiles and clinical data of GC patients were obtained from The Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) database. A pyroptosis-related lncRNA signature was constructed based on TCGA databases by using the Least Absolute Shrinkage and Selection Operator (LASSO) method Cox regression model. GC patients from the GSE62254 database cohort were used for validation. Univariate and multivariate Cox analyses were used to determine the independent predictors for OS. Gene set enrichment analyses were performed to explore the potential regulatory pathways. The immune cell infiltration level was analyzed via CIBERSORT.
    Results: A four-pyroptosis-related lncRNA (ACVR2B-AS1, PRSS30P, ATP2B1-AS1, RMRP) signature was constructed using LASSO Cox regression analysis. GC patients were stratified into high- and low-risk groups, and patients in the high-risk group showed significant worse prognosis in TNM stage, gender, and age. The risk score was an independent predictor for OS by multivariate Cox analysis. Functional analysis indicated that the immune cell infiltrate was different between high- and low-risk groups.
    Conclusion: The pyroptosis-related lncRNA prognostic signature can be used for predicting prognosis in GC. Moreover, the novel signature might provide clinical therapeutic intervention for GC patients.
    Keywords:  LncRNA content; biomarker; gastric cancer; prognostic prediction; pyroptosis; signature
    DOI:  https://doi.org/10.3389/fendo.2023.1120216
  86. Front Oncol. 2023 ;13 1099550
    MS0621, a novel small-molecule modulator of Ewing sarcoma chromatin accessibility, interacts with an RNA-associated macromolecular complex and influences RNA splicing.
    Tamara Vital, Aminah Wali, Kyle V Butler, Yan Xiong, Joseph P Foster, Shelsa S Marcel, Andrew W McFadden, Valerie U Nguyen, Benton M Bailey, Kelsey N Lamb, Lindsey I James, Stephen V Frye, Amber L Mosely, Jian Jin, Samantha G Pattenden, Ian J Davis.
      Ewing sarcoma is a cancer of children and young adults characterized by the critical translocation-associated fusion oncoprotein EWSR1::FLI1. EWSR1::FLI1 targets characteristic genetic loci where it mediates aberrant chromatin and the establishment of de novo enhancers. Ewing sarcoma thus provides a model to interrogate mechanisms underlying chromatin dysregulation in tumorigenesis. Previously, we developed a high-throughput chromatin-based screening platform based on the de novo enhancers and demonstrated its utility in identifying small molecules capable of altering chromatin accessibility. Here, we report the identification of MS0621, a molecule with previously uncharacterized mechanism of action, as a small molecule modulator of chromatin state at sites of aberrant chromatin accessibility at EWSR1::FLI1-bound loci. MS0621 suppresses cellular proliferation of Ewing sarcoma cell lines by cell cycle arrest. Proteomic studies demonstrate that MS0621 associates with EWSR1::FLI1, RNA binding and splicing proteins, as well as chromatin regulatory proteins. Surprisingly, interactions with chromatin and many RNA-binding proteins, including EWSR1::FLI1 and its known interactors, were RNA-independent. Our findings suggest that MS0621 affects EWSR1::FLI1-mediated chromatin activity by interacting with and altering the activity of RNA splicing machinery and chromatin modulating factors. Genetic modulation of these proteins similarly inhibits proliferation and alters chromatin in Ewing sarcoma cells. The use of an oncogene-associated chromatin signature as a target allows for a direct approach to screen for unrecognized modulators of epigenetic machinery and provides a framework for using chromatin-based assays for future therapeutic discovery efforts.
    Keywords:  Ewing sarcoma (ES); RNA-binding proteins; RNA-processing; SWI/SNF (BAF) complex; chromatin; drug discovery
    DOI:  https://doi.org/10.3389/fonc.2023.1099550
  87. Biophys J. 2023 Feb 10. pii: S0006-3495(22)02586-3. [Epub ahead of print]122(3S1): 295a
    RNA structure controls composition and network dynamics of condensates.
    Ian Seim, Austin J Graham, Arnold Mathijssen, Amy S Gladfelter.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.1670
  88. Adv Healthc Mater. 2023 Feb 13. e2202688
    Polymer-based mRNA delivery strategies for advanced therapies.
    Wenqian Yang, Lucas Mixich, Eger Boonstra, Horacio Cabral.
      Messenger RNA (mRNA) based therapies offer great promise for the treatment of a variety of diseases. In 2020, two FDA approvals of mRNA-based vaccines have elevated mRNA vaccines to global recognition. However, the therapeutic capabilities of mRNA extend far beyond vaccines against infectious diseases. They hold potential for cancer vaccines, protein replacement therapies, gene editing therapies, and immunotherapies. For realizing such advanced therapies, it is crucial to develop effective carrier systems. Recent advances in material science have led to the development of promising non-viral mRNA delivery systems. In comparison to other carriers like lipid nanoparticles, polymer-based delivery systems often receive less attention, despite their unique ability to carefully tune their chemical features to promote mRNA protection, their favorable pharmacokinetics, and their potential for targeting delivery. In this review, we discuss the central features of polymer-based systems for mRNA delivery highlighting the molecular design criteria, stability, and biodistribution. Finally, we analyze the role of targeting ligands for the future of RNA therapies. This article is protected by copyright. All rights reserved.
    Keywords:  ligand-mediated targeting; messenger RNA; polymer-based delivery systems
    DOI:  https://doi.org/10.1002/adhm.202202688
  89. Pathol Res Pract. 2023 Feb 03. pii: S0344-0338(23)00051-1. [Epub ahead of print]243 154351
    A review on the role of LINC00173 in human cancers.
    Soudeh Ghafouri-Fard, Arash Safarzadeh, Bashdar Mahmud Hussen, Mohammed Fatih Rasul, Mohammad Taheri, Nader Akbari Dilmaghani.
      Long intergenic non-protein coding RNA 173 (LINC00173) is a long non-coding RNA with especial function in the tumorigenic process. Studies in different types of cancers support an oncogenic role for LINC00173 except for studies in B-cell precursor acute lymphoblastic leukemia, cervical cancer, pancreatic cancer and gastric cancer. In breast and lung cancers, both oncogenic and tumor suppressor roles have been reported for LINC00173. LINC00173 can serve as a molecular sponge for miRNAs. miR-218/Etk, miR-511-5p/VEGFA, miR-182-5p/AGER, miR-765/NUTF2, miR-765/PLP2, miR-182-5p/FBXW7, miR-338-3p/Rab25, miR‑641/RAB14 and miR-1275/BCL2 are examples of the miRNA/mRNA axes being regulated by LINC00173 in the context of cancer. The current review provides a summary of different studies on the role of LINC00173 in these cancers.
    Keywords:  Biomarker; Cancer; LINC00173
    DOI:  https://doi.org/10.1016/j.prp.2023.154351
  90. Curr Genomics. 2022 Aug 11. 23(4): 262-274
    Construction of PARPi Resistance-related Competing Endogenous RNA Network.
    Lili Kong, Jiaqi Xu, Lijun Yu, Shuo Liu, Zongjian Liu, Juanjuan Xiang.
      Objective: Ovarian cancer is a kind of common gynecological malignancy in women. PARP inhibitors (PARPi) have been approved for ovarian cancer treatment. However, the primary and acquired resistance have limited the application of PARPi. The mechanisms remain to be elucidated. Methods: In this study, we characterized the expression profiles of mRNA and nonconding RNAs (ncRNAs) and constructed the regulatory networks based on RNA sequencing in PARPi Olaparib-induced ovarian cancer cells. Results: We found that the functions of the differentially expressed genes were enriched in "PI3K/AKT signaling pathway," "MAPK signaling pathway" and "metabolic process". The functions of DELs (cis) were enriched in "Human papillomavirus infection""tight junction" "MAPK signaling pathway". As the central regulator of ceRNAs, the differentially expressed miRNAs were enriched in "Human papillomavirus infection" "MAPK signaling pathway" "Ras signaling pathway". According to the degree of interaction, we identified 3 lncRNAs, 2 circRNAs, 7 miRNAs, and 12 mRNA as the key regulatory ceRNA axis, in which miR-320b was the important mediator. Conclusion: Here, we revealed the key regulatory lncRNA (circRNA)-miRNA-mRNA axis and their involved pathways in the PARPi resistant ovarian cancer cells. These findings provide new insights into exploring the ceRNA regulatory networks and developing new targets for PARPi resistance.
    Keywords:  DNA; Ovarian cancer; PARPi resistance; SSB; ceRNA network; mRNA
    DOI:  https://doi.org/10.2174/1389202923666220527114108
  91. BMC Biol. 2023 Feb 16. 21(1): 35
    Gene expression differences consistent with water loss reduction underlie desiccation tolerance of natural Drosophila populations.
    Vivien Horváth, Sara Guirao-Rico, Judit Salces-Ortiz, Gabriel E Rech, Llewellyn Green, Eugenio Aprea, Mirco Rodeghiero, Gianfranco Anfora, Josefa González.
       BACKGROUND: Climate change is one of the main factors shaping the distribution and biodiversity of organisms, among others by greatly altering water availability, thus exposing species and ecosystems to harsh desiccation conditions. However, most of the studies so far have focused on the effects of increased temperature. Integrating transcriptomics and physiology is key to advancing our knowledge on how species cope with desiccation stress, and these studies are still best accomplished in model organisms.
    RESULTS: Here, we characterized the natural variation of European D. melanogaster populations across climate zones and found that strains from arid regions were similar or more tolerant to desiccation compared with strains from temperate regions. Tolerant and sensitive strains differed not only in their transcriptomic response to stress but also in their basal expression levels. We further showed that gene expression changes in tolerant strains correlated with their physiological response to desiccation stress and with their cuticular hydrocarbon composition, and functionally validated three of the candidate genes identified. Transposable elements, which are known to influence stress response across organisms, were not found to be enriched nearby differentially expressed genes. Finally, we identified several tRNA-derived small RNA fragments that differentially targeted genes in response to desiccation stress.
    CONCLUSIONS: Overall, our results showed that basal gene expression differences across individuals should be analyzed if we are to understand the genetic basis of differential stress survival. Moreover, tRNA-derived small RNA fragments appear to be relevant across stress responses and allow for the identification of stress-response genes not detected at the transcriptional level.
    Keywords:  Cuticular hydrocarbons; Insect physiology; Post-transcriptional regulation; Respiration rate; Water content; tRFs
    DOI:  https://doi.org/10.1186/s12915-023-01530-4
  92. Biophys J. 2023 Feb 10. pii: S0006-3495(22)01990-7. [Epub ahead of print]122(3S1): 171a-172a
    Multivalent interactions between RNA and RNA binding proteins drive differential intra-speckle positioning of RNA transcripts.
    Sneha Paul, Mauricio A Heranandez, Li Wen, Susan Liao, Jiacheng Zhang, Xiaoshu Wang, Oded Regev, Jingyi Fei.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.1074
  93. Lab Invest. 2022 09;pii: S0023-6837(22)00276-8. [Epub ahead of print]102(9): 1000-1010
    Leukemia/lymphoma-related factor (LRF) or osteoclast zinc finger protein (OCZF) overexpression promotes osteoclast survival by increasing Bcl-xl mRNA: A novel regulatory mechanism mediated by the RNA binding protein SAM68.
    Xianghe Xu, Takeo Shobuike, Makoto Shiraki, Asana Kamohara, Hirohito Hirata, Masatoshi Murayama, Daisuke Mawatari, Masaya Ueno, Tadatsugu Morimoto, Toshio Kukita, Masaaki Mawatari, Akiko Kukita.
      RANKL induces NFATc1, a key transcriptional factor to induce osteoclast-specific genes such as cathepsin K, whereas transcriptional control of osteoclast survival is not fully understood. Leukemia/lymphoma-related factor (LRF) in mouse and osteoclast zinc finger protein (OCZF) in rat are zinc finger and BTB domain-containing protein (zBTB) family of transcriptional regulators, and are critical regulators of hematopoiesis. We have previously shown that differentiation and survival were enhanced in osteoclasts from OCZF-Transgenic (Tg) mice. In the present study, we show a possible mechanism of osteoclast survival regulated by LRF/OCZF and the role of OCZF overexpression in pathological bone loss. In the in vitro cultures, LRF was highly colocalized with NFATc1 in cells of early stage in osteoclastogenesis, but only LRF expression persisted after differentiation into mature osteoclasts. LRF expression was further enhanced in resorbing osteoclasts formed on dentin slices. Osteoclast survival inhibitor such as alendronate, a bisphosphonate reduced LRF expression. Micro CT evaluation revealed that femurs of OCZF-Tg mice showed significantly lower bone volume compared to that of WT mice. Furthermore, OCZF overexpression markedly promoted bone loss in ovariectomy-induced osteolytic mouse model. The expression of anti-apoptotic Bcl-xl mRNA, which is formed by alternative splicing, was enhanced in the cultures in which osteoclasts are formed from OCZF-Tg mice. In contrast, the expression of pro-apoptotic Bcl-xs mRNA was lost in the culture derived from OCZF-Tg mice. We found that the expression levels of RNA binding splicing regulator, Src substrate associated in mitosis of 68 kDa (Sam68) protein were markedly decreased in OCZF-Tg mice-derived osteoclasts. In addition, shRNA-mediated knockdown of Sam68 expression increased the expression of Bcl-xl mRNA, suggesting that SAM68 regulates the expression of Bcl-xl. These results indicate that OCZF overexpression reduces protein levels of Sam68, thereby promotes osteoclast survival, and suggest that LRF/OCZF is a promising target for regulating pathological bone loss.
    DOI:  https://doi.org/10.1038/s41374-022-00792-w
  94. Biophys J. 2023 Feb 10. pii: S0006-3495(22)03172-1. [Epub ahead of print]122(3S1): 415a-416a
    The role of RNA condensation in reducing gene expression noise.
    Alexander J Mayer, Marcus Roper, Amy S Gladfelter, Grace McLaughlin.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.2256
  95. Front Oncol. 2023 ;13 1097956
    Emerging landscape of circFNDC3B and its role in human malignancies.
    Kai Sun, Huibao Yao, Peizhi Zhang, Yanning Sun, Jian Ma, Qinghua Xia.
      In recent years, more attention has been paid to expanding the abundance of Circular RNAs (circRNAs), while the circRNAs that have been found to have significant functions have not been studied in different diseases. CircFNDC3B is one of the most researched circRNAs generated from fibronectin type III domain-containing protein 3B (FNDC3B) gene. Accumulating researches have reported the multiple functions of circFNDC3B in different cancer types and other non-neoplastic diseases, and predicted that circFNDC3B might be a potential biomarker. Notably, circFNDC3B can play roles in different diseases by binding to various microRNAs (miRNAs), binding to RNA-binding proteins (RBPs), or encoding functional peptides. This paper systematically summarizes the biogenesis and function of circRNAs, reviews and discusses the roles and molecular mechanisms of circFNDC3B and its target genes in different cancers and non-neoplastic diseases, which will do favor to broaden our comprehension of the function of circRNAs and facilitate subsequent research on circFNDC3B.
    Keywords:  biomarker; cancers; circFNDC3B; circRNAs; diseases
    DOI:  https://doi.org/10.3389/fonc.2023.1097956
  96. Biophys J. 2023 Feb 10. pii: S0006-3495(22)03506-8. [Epub ahead of print]122(3S1): 484a
    RNA secondary structure modulates the co-translational association of hERG1a and 1b mRNAs.
    Lisandra Flores Aldama, Breanna L Raab, Erick B Rios Perez, Fang Liu, Gail A Robertson.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.2590
  97. Front Pharmacol. 2023 ;14 1105484
    Emerging role of non-coding RNAs in resistance to platinum-based anti-cancer agents in lung cancer.
    Priya Mondal, Syed Musthapa Meeran.
      Platinum-based drugs are the first line of therapeutics against many cancers, including lung cancer. Lung cancer is one of the leading causes of cancer-related death worldwide. Platinum-based agents target DNA and prevent replication, and transcription, leading to the inhibition of cell proliferation followed by cellular apoptosis. About twenty-three platinum-based drugs are under different stages of clinical trials, among cisplatin, carboplatin, and oxaliplatin are widely used for the treatment of various cancers. Among them, cisplatin is the most commonly used drug for cancer therapy, which binds with RNA, and hinders the cellular RNA process. However, long-term use of platinum-based drugs can cause different side effects and has been shown to develop chemoresistance, leading to poor clinical outcomes. Chemoresistance became an important challenge for cancer treatment. Platinum-based chemoresistance occurs due to the influence of intrinsic factors such as overexpression of multidrug resistance proteins, advancement of DNA repair mechanism, degradation, and deactivation of intracellular thiols. Recently, epigenetic modifications, especially non-coding RNAs (ncRNAs) mediated gene regulation, grasp the attention for reversing the sensitivity of platinum-based drugs due to their reversible nature without altering genome sequence. ncRNAs can also modulate the intrinsic and non-intrinsic mechanisms of resistance in lung cancer cells. Therefore, targeting ncRNAs could be an effective approach for developing novel therapeutics to overcome lung cancer chemoresistance. The current review article has discussed the role of ncRNA in chemoresistance and its underlying molecular mechanisms in human lung cancer.
    Keywords:  carboplatin; chemoresistance; cisplain; microRNA; non-coding RNAs; platinum drugs; platinum resistant cancer
    DOI:  https://doi.org/10.3389/fphar.2023.1105484
  98. Lab Invest. 2021 Aug;pii: S0023-6837(22)00594-3. [Epub ahead of print]101(8): 1011-1025
    MicroRNA-432-5p regulates sprouting and intussusceptive angiogenesis in osteosarcoma microenvironment by targeting PDGFB.
    Selvaraj Vimalraj, Raghunandhakumar Subramanian, Sekaran Saravanan, Balasubramanian Arumugam, Dhanasekaran Anuradha.
      Osteosarcoma (OS) is a type of bone tumor conferred with high metastatic potential. Attainable growth of tumors necessitates functional vasculature mediated by sprouting angiogenesis (SA) and intussusceptive angiogenesis (IA). However, the regulation of IA and SA is still unclear in OS. To understand the mechanisms adopted by OS to induce angiogenesis, initially, we assessed the expression profile of a set of miRNAs' in both OS cells (SaOS2 and MG63) and normal bone cells. Amongst them, miR-432-5p was found to be highly downregulated in OS. The functional role of miR-432-5p in OS was further analyzed using miR-432-5p mimic/inhibitor. Platelet-derived growth factor-B (PDGFB) was found to be a putative target of miR-432-5p and it was further confirmed that the PDGFB 3'UTR is directly targeted by miR-432-5p using the luciferase reporter gene system. PDGFB was found to be secreted by OS to regulate angiogenesis by targeting the cells in its microenvironment. The conditioned medium obtained from miR-432-5p mimic transfected MG63 and SaOS2 cells decreased cell viability, proliferation, migration, and aorta ring formation in endothelial cells. The miRNA mimic/inhibitor transfected MG63 and SaOS2 cells were placed on SA (day 6) and IA (day 9) phase of CAM development to analyze SA and IA mechanisms. It was found that miR-432-5p mimic transfection in OS promotes the transition of SA to IA which was documented by the angiogenic parameters and SA and IA-associated gene expression. Interestingly, this outcome was also supported by the zebrafish tumor xenograft model. Corroborating these results, it is clear that miR-432-5p expression in OS cells regulates SA and IA by targeting PDGFB genes. We conclude that targeting miR-432-5p/PDGFB signaling can be a potential therapeutic strategy to treat OS along with other existing strategies. MicroRNA-432-5p expression in osteosarcoma cells regulates sprouting and intussusceptive angiogenesis by targeting PDGFB genes. MicroRNA-432-5p/PDGFB signaling can be targeted to treat angiogenesis in osteosarcoma along with other strategies which will further strengthen the effectiveness of antiangiogenic therapy.
    DOI:  https://doi.org/10.1038/s41374-021-00589-3
  99. Comb Chem High Throughput Screen. 2023 Feb 13.
    Long Non-coding RNA XIST Impedes LPS-induced AC16 Cell Inflammation and Apoptosis through Down-regulating miR-370-3p and Regulating PI3K/AKT/mTOR Pathways.
    Jun Xiao, Min Qiu, Mingzhi Long, Shushu Zhou, Shouyu Guo, Shaohua Xu, Hai Jiang.
       BACKGROUND/PURPOSE: Myocarditis is a severe disorder characterized by the inflammation of the heart's muscular walls, thereby leading to sudden death in young adults. Long non-coding RNA X-inactive specific transcripts (LncRNA XIST) are a class of transcripts having a length ˃ 200 nts with the absence of protein-coding abilities. They exert their function of apoptosis in various cancers and inflammatory diseases.
    OBJECTIVE: The current work intended to investigate the impact and mechanism of XIST on inflammation induced by LPS in AC16 cells.
    METHODS: An in vitro inflammatory injury model was established by stimulating AC16 cells with LPS. CCK-8 was used to test AC16 cell viability and FCM to detect apoptosis. The Elisa assay was used to measure the level of IL-8, IL-1β, and TNF-α. The RT-qPCR was used to detect XIST, miR-370-3p, Bax, and Bcl-2 in LPS-stimulated AC16 cells. The Elisa assay was performed to assess the phosphorylation of PI3K, AKT and mTOR in AC16 cells.
    RESULTS: Our findings showed LPS exposure to significantly reduce AC16 cell viability while increasing inflammation and apoptosis. Also, XIST expression was reduced in AC16 cells stimulated with LPS. Overexpression of XIST in AC16 cells increased cell survival, inhibited apoptosis, and increased the expressions of Bcl-2, Bax, and inflammatory modulators (IL-8, TNF-α, and IL-1β). Inhibiting XIST in AC16 cells produced opposite outcomes. MiR-370-3p mimics inhibited XIST's effect on inflammation, viability, and apoptosis. Moreover, XIST inhibited the phosphorylation levels of mTOR, AKT, and PI3K in LPS-injured AC16 cells.
    CONCLUSION: The data elucidate lncRNA XIST to exert its anti-inflammatory and anti-apoptotic effects on AC16 cells stimulated by LPS via down-regulating miR-370-3p and inhibiting PI3K/AKT/mTOR pathways. These findings suggest a novel treatment strategy for myocarditis.
    Keywords:  PI3K/AKT/mTOR; RNA XIST; apoptosis; apoptosisRNA XIST; inflammation; miR-370-3p
    DOI:  https://doi.org/10.2174/1386207326666230213124031
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