bims-lorfki Biomed News
on Long non-coding RNA functions in the kidney
Issue of 2020–12–13
seven papers selected by
Nikita Dewani, Max Delbrück Centre for Molecular Medicine
  1. Genomic Fabric Remodeling in Metastatic Clear Cell Renal Cell Carcinoma (ccRCC): A New Paradigm and Proposal for a Personalized Gene Therapy Approach.
  2. Long Noncoding RNA/Circular RNA-miRNA-mRNA Axes in Ischemia-Reperfusion Injury.
  3. The computational approaches of lncRNA identification based on coding potential: Status quo and challenges.
  4. Aberrant Non-Coding RNA Expression in Patients with Systemic Lupus Erythematosus: Consequences for Immune Dysfunctions and Tissue Damage.
  5. DMDRMR-mediated regulation of m6A-modified CDK4 by m6A reader IGF2BP3 drives ccRCC progression.
  6. Long non-coding RNA Kcnq1ot1 promotes sC5b-9-induced podocyte pyroptosis by inhibiting miR-486a-3p and upregulating NLRP3.
  7. Total Glucosides of Paeony Alleviate Cell Apoptosis and Inflammation by Targeting the Long Noncoding RNA XIST/MicroRNA-124-3p/ITGB1 Axis in Renal Ischemia/Reperfusion Injury.
  1. Cancers (Basel). 2020 Dec 08. pii: E3678. [Epub ahead of print]12(12):
    Genomic Fabric Remodeling in Metastatic Clear Cell Renal Cell Carcinoma (ccRCC): A New Paradigm and Proposal for a Personalized Gene Therapy Approach.
    Dumitru A Iacobas, Victoria E Mgbemena, Sanda Iacobas, Kareena M Menezes, Huichen Wang, Premkumar B Saganti.
      Published transcriptomic data from surgically removed metastatic clear cell renal cell carcinoma samples were analyzed from the genomic fabric paradigm (GFP) perspective to identify the best targets for gene therapy. GFP considers the transcriptome as a multi-dimensional mathematical object constrained by a dynamic set of expression controls and correlations among genes. Every gene in the chest wall metastasis, two distinct cancer nodules, and the surrounding normal tissue of the right kidney was characterized by three independent measures: average expression level, relative expression variation, and expression correlation with each other gene. The analyses determined the cancer-induced regulation, control, and remodeling of the chemokine and vascular endothelial growth factor (VEGF) signaling, apoptosis, basal transcription factors, cell cycle, oxidative phosphorylation, renal cell carcinoma, and RNA polymerase pathways. Interestingly, the three cancer regions exhibited different transcriptomic organization, suggesting that the gene therapy should not be personalized only for every patient but also for each major cancer nodule. The gene hierarchy was established on the basis of gene commanding height, and the gene master regulators DAPK3,TASOR, FAM27C and ALG13 were identified in each profiled region. We delineated the molecular mechanisms by which TASOR overexpression and ALG13 silencing would selectively affect the cancer cells with little consequences for the normal cells.
    Keywords:  ALG13; FAM27C; TASOR; VEGF signaling; VHL; basal transcription factors; cell cycle; chemokine signaling; genomic medicine; kidney cancer
    DOI:  https://doi.org/10.3390/cancers12123678
  2. Biomed Res Int. 2020 ;2020 8838524
    Long Noncoding RNA/Circular RNA-miRNA-mRNA Axes in Ischemia-Reperfusion Injury.
    Chengwu Gong, Xueliang Zhou, Songqing Lai, Lijun Wang, Jichun Liu.
      Ischemia-reperfusion injury (IRI) elicits tissue injury involved in a wide range of pathologies. Multiple studies have demonstrated that noncoding RNAs (ncRNAs), including long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs), participate in the pathological development of IRI, and they may act as biomarkers, therapeutic targets, or prognostic indicators. Nonetheless, the specific molecular mechanisms of ncRNAs in IRI have not been completely elucidated. Regulatory networks among lncRNAs/circRNAs, miRNAs, and mRNAs have been the focus of attention in recent years. Studies on the underlying molecular mechanisms have contributed to the discovery of therapeutic targets or strategies in IRI. In this review, we comprehensively summarize the current research on the lncRNA/circRNA-miRNA-mRNA axes and highlight the important role of these axes in IRI.
    DOI:  https://doi.org/10.1155/2020/8838524
  3. Comput Struct Biotechnol J. 2020 ;18 3666-3677
    The computational approaches of lncRNA identification based on coding potential: Status quo and challenges.
    Jing Li, Xuan Zhang, Changning Liu.
      Long noncoding RNAs (lncRNAs) make up a large proportion of transcriptome in eukaryotes, and have been revealed with many regulatory functions in various biological processes. When studying lncRNAs, the first step is to accurately and specifically distinguish them from the colossal transcriptome data with complicated composition, which contains mRNAs, lncRNAs, small RNAs and their primary transcripts. In the face of such a huge and progressively expanding transcriptome data, the in-silico approaches provide a practicable scheme for effectively and rapidly filtering out lncRNA targets, using machine learning and probability statistics. In this review, we mainly discussed the characteristics of algorithms and features on currently developed approaches. We also outlined the traits of some state-of-the-art tools for ease of operation. Finally, we pointed out the underlying challenges in lncRNA identification with the advent of new experimental data.
    Keywords:  Algorithm; Coding potential; Feature; In sillico; LncRNA identification; sORF
    DOI:  https://doi.org/10.1016/j.csbj.2020.11.030
  4. Biomolecules. 2020 Dec 06. pii: E1641. [Epub ahead of print]10(12):
    Aberrant Non-Coding RNA Expression in Patients with Systemic Lupus Erythematosus: Consequences for Immune Dysfunctions and Tissue Damage.
    Chang-Youh Tsai, Chieh-Yu Shen, Chih-Wei Liu, Song-Chou Hsieh, Hsien-Tzung Liao, Ko-Jen Li, Cheng-Shiun Lu, Hui-Ting Lee, Cheng-Sung Lin, Cheng-Han Wu, Yu-Min Kuo, Chia-Li Yu.
      Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease with heterogeneous clinical manifestations. A diverse innate and adaptive immune dysregulation is involved in the immunopathogenesis of SLE. The dysregulation of immune-related cells may derive from the intricate interactions among genetic, epigenetic, environmental, and immunological factors. Of these contributing factors, non-coding RNAs (ncRNAs), including microRNAs (miRNAs, miRs), and long non-coding RNAs (lncRNAs) play critical roles in the post-transcriptional mRNA expression of cytokines, chemokines, and growth factors, which are essential for immune modulation. In the present review, we emphasize the roles of ncRNA expression in the immune-related cells and cell-free plasma, urine, and tissues contributing to the immunopathogenesis and tissue damage in SLE. In addition, the circular RNAs (circRNA) and their post-translational regulation of protein synthesis in SLE are also briefly described. We wish these critical reviews would be useful in the search for biomarkers/biosignatures and novel therapeutic strategies for SLE patients in the future.
    Keywords:  SLE; autoimmunity; circRNA; epigenetic regulation; lncRNA; miRNA; ncRNA
    DOI:  https://doi.org/10.3390/biom10121641
  5. Cancer Res. 2020 Dec 08. pii: canres.1619.2020. [Epub ahead of print]
    DMDRMR-mediated regulation of m6A-modified CDK4 by m6A reader IGF2BP3 drives ccRCC progression.
    Shan Gao, Yinmin Gu, Shaoxi Niu, Yang Wang, Liqiang Duan, Yongbo Pan, Zhou Tong, Xu Zhang, Zhenyu Yang, Bo Peng, Xiaodong Wang, Xiaoqi Han, Yuxin Li, Tianyou Cheng, Yajuan Liu, Lina Shang, Tongfeng Liu, Xiwang Yang, Minxuan Sun, Siyuan Jiang, Chang Zhang, Ning Zhang, Qinong Ye.
      Aberrant N6-methyladenosine (m6A) modification has emerged as a driver of tumor initiation and progression, yet how lncRNA are involved in the regulation of m6A remains unknown. Here we utilize data from 12 cancer types from The Cancer Genome Atlas to comprehensively map lncRNA that are potentially deregulated by DNA methylation. A novel DNA methylation-deregulated and RNA m6A reader-cooperating lncRNA (DMDRMR) facilitated tumor growth and metastasis in clear cell renal cell carcinoma (ccRCC). Mechanistically, DMDRMR bound insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) to stabilize target genes, including the cell cycle kinase CDK4 and three extracellular matrix components (COL6A1, LAMA5, and FN1), by specifically enhancing IGF2BP3 activity on them in an m6A-dependent manner. Consequently, DMDRMR and IGF2BP3 enhanced the G1/S transition, thus promoting cell proliferation in ccRCC. In ccRCC patients, high coexpression of DMDRMR and IGF2BP3 was associated with poor outcomes. Our findings reveal that DMDRMR cooperates with IGF2BP3 to regulate target genes in an m6A-dependent manner and may represent a potential diagnostic, prognostic, and therapeutic target in ccRCC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-1619
  6. Am J Physiol Cell Physiol. 2020 Dec 09.
    Long non-coding RNA Kcnq1ot1 promotes sC5b-9-induced podocyte pyroptosis by inhibiting miR-486a-3p and upregulating NLRP3.
    Chunjian Zhang, Yimeng Gong, Na Li, Xiaoyan Liu, Yunzhu Zhang, Fangze Ye, Qiang Guo, Jiaxin Zheng.
      Podocytes are epithelial cells adhering glomerular capillaries, which regulate the integrity of glomerular filtration barrier. Irreversible podocyte injury induces glomerular inflammation and causes chronic renal diseases. Kcnq1ot1, a long non-coding RNA (lncRNA), participates in the pathogenesis of diabetic retinopathy and cardiomyopathy. However, its function in podocyte injury is elusive. Pyroptosis of murine podocyte MPC5 was triggered by sublytic complement C5b-9 (sC5b-9) for subsequent in vitro functional and mechanistic investigation. Gain/Loss-of-function analysis was conducted to examine the functional role of Kcnq1ot1 in podocyte pyroptosis. Meanwhile, the molecular mechanism of Kcnq1ot1's effect on podocyte injury was explored by identifying downstream molecules and their intermediate interactions. Kcnq1ot1 was upregulated in sC5b-9-induced podocytes, and silencing Kcnq1ot1 could inhibit sC5b-9's effect on podocyte pyroptosis. We also identified the interaction between Kcnq1ot1 and miR-486a-3p, through which Kcnq1ot1 mediated miR-486a-3p inhibition by sC5b-9. Furthermore, miR-486a-3p reduced the transcriptional activity of NLRP3, while the overexpression of NLRP3 enhanced sC5b-9's effect on podocyte pyroptosis through activating NLRP3 inflammasome. sC5b-9 induces pyroptosis in podocytes through modulating the Kcnq1ot1/miR-486a-3p/NLRP3 regulatory axis, and these uncovered key molecules might facilitate podocyte-targeted treatment for renal inflammatory diseases.
    DOI:  https://doi.org/10.1152/ajpcell.00403.2020
  7. Mediators Inflamm. 2020 ;2020 8869511
    Total Glucosides of Paeony Alleviate Cell Apoptosis and Inflammation by Targeting the Long Noncoding RNA XIST/MicroRNA-124-3p/ITGB1 Axis in Renal Ischemia/Reperfusion Injury.
    Fang Chen, Yi Hu, Yuetao Xie, Zonghui Zhao, Lin Ma, Zhili Li, Wanlong Tan.
       Objective: Renal ischemia/reperfusion injury (RI/RI) is the main cause of acute kidney injury. Total glucosides of paeony (TGP) are a traditional Chinese medicine. This study was aimed at exploring the role of TGP in RI/RI and its underlying mechanism of action.
    Methods: Rat RI/RI models were constructed by surgical operation. Serum creatinine (Scr) and blood urea nitrogen (BUN) were used to evaluate renal function. The levels of proinflammatory cytokines were detected by ELISA. RI/RI was simulated by hypoxia/reoxygenation (H/R) treatment in renal cells in vitro. The lncRNA XIST (XIST) expression was analyzed by qRT-PCR. Then, the viability and apoptosis of renal cells were detected by MTT and flow cytometry assay. Additionally, dual-luciferase reporter assay was used to determine the interactions among XIST, microRNA-124-3p (miR-124-3p), and ITGB1.
    Results: TGP improved renal function and inhibited inflammatory responses after RI/RI. XIST expression was highly expressed in rat RI/RI models and H/R-treated renal cells, whereas treatment with TGP downregulated the XIST expression. Additionally, TGP increased viability and attenuated apoptosis and inflammation of H/R-treated renal cells via inhibiting XIST. Moreover, XIST was competitively bound to miR-124-3p, and ITGB1 was a target of miR-124-3p. miR-124-3p overexpression or ITGB1 inhibition rescued the reduction effect on viability and mitigated the promoting effects on cell apoptosis and inflammation caused by XIST overexpression in H/R-treated renal cells.
    Conclusions: In vivo, TGP attenuated renal dysfunction and inflammation in RI/RI rats. In vitro, TGP inhibited XIST expression to modulate the miR-124-3p/ITGB1 axis, alleviating the apoptosis and inflammation of H/R-treated renal cells.
    DOI:  https://doi.org/10.1155/2020/8869511
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