bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2021‒08‒22
nineteen papers selected by
Ankita Daiya
BITS Pilani

  1. Protein Cell. 2021 Aug 17.
      Tumors are complex ecosystems in which heterogeneous cancer cells interact with their microenvironment composed of diverse immune, endothelial, and stromal cells. Cancer biology had been studied using bulk genomic and gene expression profiling, which however mask the cellular diversity and average the variability among individual molecular programs. Recent advances in single-cell transcriptomic sequencing have enabled a detailed dissection of tumor ecosystems and promoted our understanding of tumorigenesis at single-cell resolution. In the present review, we discuss the main topics of recent cancer studies that have implemented single-cell RNA sequencing (scRNA-seq). To study cancer cells, scRNA-seq has provided novel insights into the cancer stem-cell model, treatment resistance, and cancer metastasis. To study the tumor microenvironment, scRNA-seq has portrayed the diverse cell types and complex cellular states of both immune and non-immune cells interacting with cancer cells, with the promise to discover novel targets for future immunotherapy.
    Keywords:  cancer; single-cell transcriptomic sequencing; tumor microenvironment
  2. Cancer Biol Med. 2021 Aug 17. pii: j.issn.2095-3941.2020.0762. [Epub ahead of print]
      Tumor tissues contain both tumor and non-tumor cells, which include infiltrated immune cells and stromal cells, collectively called the tumor microenvironment (TME). Single-cell RNA sequencing (scRNAseq) enables the examination of heterogeneity of tumor cells and TME. In this review, we examined scRNAseq datasets for multiple cancer types and evaluated the heterogeneity of major cell type composition in different cancer types. We further showed that endothelial cells and fibroblasts/myofibroblasts in different cancer types can be classified into common subtypes, and the subtype composition is clearly associated with cancer characteristic and therapy response.
    Keywords:  Stromal cells; pan-cancer single-cell RNA sequencing data; tumor microenvironment
  3. Front Oncol. 2021 ;11 700947
      Over decades of studies, accumulating evidence has suggested that epigenetic dysregulation is a hallmark of tumours. Post-translational modifications of histones are involved in tumour pathogenesis and development mainly by influencing a broad range of physiological processes. Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are pivotal epigenetic modulators that regulate dynamic processes in the acetylation of histones at lysine residues, thereby influencing transcription of oncogenes and tumour suppressor genes. Moreover, HDACs mediate the deacetylation process of many nonhistone proteins and thus orchestrate a host of pathological processes, such as tumour pathogenesis. In this review, we elucidate the functions of HDACs in cancer.
    Keywords:  cancer; epigenetics; histone deacetylases; protein acetylation; tumorigenesis
  4. J Mol Cell Cardiol. 2021 Aug 17. pii: S0022-2828(21)00160-7. [Epub ahead of print]
      Epigenetic modifications, such as histone or DNA modifications are key regulators of gene transcription and changes are often associated with maladaptive processes underlying cardiovascular disease. Epigenetic regulators therefore likely play a crucial role in cardiomyocyte homeostasis and facilitate the cellular adaption to various internal and external stimuli, responding to different intercellular and extracellular cues. Class IIa histone deacetylases are a class of epigenetic regulators that possess a myriad of post-transcriptional modification sites that modulate their activity in response to oxidative stress, altered catecholamine signalling or changes in the cellular metabolism. This review summaries the known reversible, post-translational modifications (PTMs) of class IIa histone deacetylases (HDACs) that ultimately drive transcriptional changes in homeostasis and disease. We also highlight the idea of a crosstalk of various PTMs on class IIa HDACs potentially leading to compensatory or synergistic effects on the class IIa HDAC-regulated cell behavior.
    Keywords:  Epigenetics; Histone deacetylases; Post-translational modifications
  5. Methods Mol Biol. 2022 ;2301 61-95
      The 3D organization of chromatin within the nucleus enables dynamic regulation and cell type-specific transcription of the genome. This is true at multiple levels of resolution: on a large scale, with chromosomes occupying distinct volumes (chromosome territories); at the level of individual chromatin fibers, which are organized into compartmentalized domains (e.g., Topologically Associating Domains-TADs), and at the level of short-range chromatin interactions between functional elements of the genome (e.g., enhancer-promoter loops).The widespread availability of Chromosome Conformation Capture (3C)-based high-throughput techniques has been instrumental in advancing our knowledge of chromatin nuclear organization. In particular, Hi-C has the potential to achieve the most comprehensive characterization of chromatin 3D interactions, as it is theoretically able to detect any pair of restriction fragments connected as a result of ligation by proximity.This chapter will illustrate how to compare the chromatin interactome in different experimental conditions, starting from pre-computed Hi-C contact matrices, how to visualize the results, and how to correlate the observed variations in chromatin interaction strength with changes in gene expression.
    Keywords:  3D chromatin structure; Bioinformatics; Differential chromatin interactions; Hi-C data
  6. Biochim Biophys Acta Rev Cancer. 2021 Aug 12. pii: S0304-419X(21)00110-4. [Epub ahead of print] 188612
      Cancer metastasis and drug resistance are two major obstacles in the treatment of cancer and therefore, the leading cause of cancer-associated mortalities worldwide. Hence, an in-depth understanding of these processes and identification of the underlying key players could help design a better therapeutic regimen to treat cancer. Earlier thought to be merely transcriptional junk and having passive or secondary function, recent advances in the genomic research have unravelled that long noncoding RNAs (lncRNAs) play pivotal roles in diverse physiological as well as pathological processes including cancer metastasis and drug resistance. LncRNAs can regulate various steps of the complex metastatic cascade such as epithelial-mesenchymal transition (EMT), invasion, migration and metastatic colonization, and also affect the sensitivity of cancer cells to various chemotherapeutic drugs. A substantial body of literature for more than a decade of research evince that lncRNAs can regulate gene expression at different levels such as epigenetic, transcriptional, posttranscriptional, translational and posttranslational levels, depending on their subcellular localization and through their ability to interact with DNA, RNA and proteins. In this review, we mainly focus on how lncRNAs affect cancer metastasis by modulating expression of key metastasis-associated genes at various levels of gene regulation. We also discuss how lncRNAs confer cancer cells either sensitivity or resistance to various chemo-therapeutic drugs via different mechanisms. Finally, we highlight the immense potential of lncRNAs as prognostic and diagnostic biomarkers as well as therapeutic targets in cancer.
    Keywords:  Cancer metastasis; Drug resistance; Gene regulation; LncRNA; Prognostic biomarker; Therapeutic target
  7. Cancer Cell Int. 2021 Aug 17. 21(1): 434
      Ovarian cancer (OC) is one of the most common malignant tumors in women. OC is associated with the activation of oncogenes, the inactivation of tumor suppressor genes, and the activation of abnormal cell signaling pathways. Moreover, epigenetic processes have been found to play an important role in OC tumorigenesis. Epigenetic processes do not change DNA sequences but regulate gene expression through DNA methylation, histone modification, and non-coding RNA. This review comprehensively considers the importance of epigenetics in OC, with a focus on microRNA and long non-coding RNA. These types of RNA are promising molecular markers and therapeutic targets that may support precision medicine in OC. DNA methylation inhibitors and histone deacetylase inhibitors may be useful for such targeting, with a possible novel approach combining these two therapies. Currently, the clinical application of such epigenetic approaches is limited by multiple obstacles, including the heterogeneity of OC, insufficient sample sizes in reported studies, and non-optimized methods for detecting potential tumor markers. Nonetheless, the application of epigenetic approaches to OC patient diagnosis, treatment, and prognosis is a promising area for future clinical investigation.
    Keywords:  DNA methylation; Epigenetics; Histone modifications; LncRNA; MiRNA; Ovarian cancer
  8. J Biomed Inform. 2021 Aug 16. pii: S1532-0464(21)00201-X. [Epub ahead of print] 103872
      OBJECTIVE: We aim to build an accurate machine learning-based system for classifying tumor attributes from cancer pathology reports in the presence of a small amount of annotated data, motivated by the expensive and time-consuming nature of pathology report annotation. An enriched labeling scheme that includes the location of relevant information along with the final label is used along with a corresponding hierarchical method for classifying reports that leverages these enriched annotations.MATERIALS AND METHODS: Our data consists of 250 colon cancer and 250 kidney cancer pathology reports from 2002-2019 at the University of California, San Francisco. For each report, we classify attributes such as procedure performed, tumor grade, and tumor site. For each attribute and document, an annotator trained by an oncologist labeled both the value of that attribute as well as the specific lines in the document that indicated the value. We develop a model that uses these enriched annotations that first predicts the relevant lines of the document, then predicts the final value given the predicted lines. We compare our model to multiple state-of-the-art methods for classifying tumor attributes from pathology reports.
    RESULTS: Our results show that across colon and kidney cancers and varying training set sizes, our hierarchical method consistently outperforms state-of-the-art methods. Furthermore, performance comparable to these methods can be achieved with approximately half the amount of labeled data.
    CONCLUSION: Document annotations that are enriched with location information are shown to greatly increase the sample efficiency of machine learning methods for classifying attributes of pathology reports.
    Keywords:  Natural Language Processing
  9. Nat Rev Mol Cell Biol. 2021 Aug 16.
      Precise control of gene expression is fundamental to cell function and development. Although ultimately gene expression relies on DNA-binding transcription factors to guide the activity of the transcription machinery to genes, it has also become clear that chromatin and histone post-translational modification have fundamental roles in gene regulation. Polycomb repressive complexes represent a paradigm of chromatin-based gene regulation in animals. The Polycomb repressive system comprises two central protein complexes, Polycomb repressive complex 1 (PRC1) and PRC2, which are essential for normal gene regulation and development. Our early understanding of Polycomb function relied on studies in simple model organisms, but more recently it has become apparent that this system has expanded and diverged in mammals. Detailed studies are now uncovering the molecular mechanisms that enable mammalian PRC1 and PRC2 to identify their target sites in the genome, communicate through feedback mechanisms to create Polycomb chromatin domains and control transcription to regulate gene expression. In this Review, we discuss and contextualize the emerging principles that define how this fascinating chromatin-based system regulates gene expression in mammals.
  10. Methods Mol Biol. 2022 ;2301 317-336
      While many computational methods have been proposed for 3D chromosome reconstruction from chromosomal contact maps, these methods are rarely used for the interpretation of such experimental data, in particular Hi-C data. We posit that this is due to the lack of an easy-to-use implementation of the proposed algorithms, as well as to the important computational cost of most methods. We here give a detailed implementation of the fast ShRec3D algorithm. We provide a tutorial that will enable the reader to reconstruct 3D consensus structures for human chromosomes and to decorate these structures with chromatin epigenetic states. We use this methodology to show that the bivalent chromatin, including Polycomb-rich domains, is spatially segregated and located in between the active and the quiescent chromatin compartments.
    Keywords:  3D reconstruction; Chromatin; Contact network; Epigenetic marks; Hi-C; Multidimensional scaling; Shortest-path distance
  11. Stem Cell Rev Rep. 2021 Aug 21.
      The "bivalent domain" is a unique histone modification region consisting of two histone tri-methylation modifications. Over the years, it has been revealed that the maintenance and dynamic changes of the bivalent domains play a vital regulatory role in the differentiation of various stem cell systems, as well as in other cells, such as immunomodulation. Tri-methylation modifications involved in the formation of the bivalent domains are interrelated and mutually regulated, thus regulating many life processes of cells. Tri-methylation of histone H3 at lysine 4 (H3K4me3), tri-methylation of histone H3 at lysine 9 (H3K9me3) and tri-methylation of histone H3 at lysine 27 (H3K27me3) are the main tri-methylation modifications involved in the formation of bivalent domains. The three form different bivalent domains in pairs. Furthermore, it is equally clear that H3K4me3 is a positive regulator of transcription and that H3K9me3/H3K27me3 are negative regulators. Enzymes related to the regulation of histone methylation play a significant role in the "homeostasis" and "breaking homeostasis" of the bivalent domains. Bivalent domains regulate target genes, upstream transcription, downstream targeting regulation and related cytokines during the establishment and breakdown of homeostasis, and exert the specific regulation of stem cells. Indeed, a unified mechanism to explain the bivalent modification in all stem cells has been difficult to define, and whether the bivalent modification is antagonistic in inducing the differentiation of homologous stem cells is controversial. In this review, we focus on the different bivalent modifications in several key stem cells and explore the main mechanisms and effects of these modifications involved. Finally, we discussed the close relationship between bivalent domains and immune cells, and put forward the prospect of the application of bivalent domains in the field of stem cells.
    Keywords:  Bivalent domain; H3K27me3; H3K4me3; H3K9me3; Immune cells; Stem cells
  12. Methods Mol Biol. 2021 ;2372 85-92
      Long noncoding RNAs (lncRNAs) exert their functions through binding to other RNA, genomic DNA, or proteins. The identification of proteins that associate with the lncRNA of interest sheds light on the molecular basis of its biological functions. This can be achieved by tagging the lncRNA with chemically modified ribonucleotides, or by using in vitro transcribed lncRNA to retrieve proteins from cell lysates. Alternatively, endogenous lncRNAs can be pulled down from cells or tissues with biotinylated antisense DNA oligonucleotides, which may overcome the potential pitfalls of using tagged lncRNAs, such as artifacts caused by tagging or non-physiological interactions. Here we describe the detailed protocol for chromatin isolation by RNA purification (ChIRP) from mammalian cell lines and mouse tissues, which captures endogenous lncRNAs and enables subsequent identification of their physiologically relevant binding partners.
    Keywords:  ChIRP; Mass spectrometry; RNA-binding protein; lncRNA
  13. Drug Discov Today. 2021 Aug 13. pii: S1359-6446(21)00362-7. [Epub ahead of print]
      Histone deacetylases (HDACs) inhibit the acetylation of crucial autophagy genes, thereby deregulating autophagy and autophagic cell death (ACD) and facilitating cancer cell survival. Vorinostat, a broad-spectrum pan-HDAC inhibitor, inhibits the deacetylation of key autophagic markers and thus interferes with ACD. Vorinostat-regulated ACD can have an autophagy-mediated, -associated or -dependent mechanism depending on the involvement of apoptosis. Molecular insights reveal that hyperactivation of the PIK3C3/VPS34-BECN1 complex increased lysosomal disparity and enhanced mitophagy. These changes were followed by reduced mitochondrial biogenesis and by secondary signals that enabled superactivated, nonselective or bulk autophagy, leading to ACD. Although the evidence is limited, this review focuses on molecular insights into vorinostat-regulated ACD and describes critical concepts for clinical translation.
    Keywords:  autophagy; cancer; cell death; histone deacetylases; vorinostat
  14. Pharmacol Res. 2021 Aug 13. pii: S1043-6618(21)00402-3. [Epub ahead of print] 105818
      Osteosarcoma is one of the most prevalent primary bone tumours with a high metastatic and recurrence rate with poor prognosis. MiRNAs are short and non-coding RNAs that could regulate various cellular activities and one of them is the epithelial-to-mesenchymal transition (EMT). Osteosarcoma cells that have undergone EMT would lose their cellular polarity and acquire invasive and metastatic characteristics. Our literature search showed that many pre-clinical and clinical studies have reported the roles of miRNAs in modulating the EMT process in osteosarcoma and compared to other cancers like breast cancer, there is a lack of review article which effectively summarizes the various roles of EMT-regulating miRNAs in osteosarcoma. This review, therefore, was aimed to discuss and summarize the EMT-promoting and EMT-suppressing roles of different miRNAs in osteosarcoma. The review would begin with the discussion on the concepts and principles of EMT, followed by the exploration of the diverse roles of EMT-regulating miRNAs in osteosarcoma. Subsequently, the potential use of miRNAs as prognostic biomarkers in osteosarcoma to predict the likelihood of metastases and as therapeutic agents would be discussed.
    Keywords:  EMT-regulating miRNAs; Osteosarcoma; biomarker; epithelial-to-mesenchymal transition (EMT); miRNAs; therapeutic agent
  15. Mol Cancer. 2021 Aug 19. 20(1): 104
      Circulating tumor cells are tumor cells with high vitality and high metastatic potential that invade and shed into the peripheral blood from primary solid tumors or metastatic foci. Due to the heterogeneity of tumors, it is difficult for high-throughput sequencing analysis of tumor tissues to find the genomic characteristics of low-abundance tumor stem cells. Single-cell sequencing of circulating tumor cells avoids interference from tumor heterogeneity by comparing the differences between single-cell genomes, transcriptomes, and epigenetic groups among circulating tumor cells, primary and metastatic tumors, and metastatic lymph nodes in patients' peripheral blood, providing a new perspective for understanding the biological process of tumors. This article describes the identification, biological characteristics, and single-cell genome-wide variation in circulating tumor cells and summarizes the application of single-cell sequencing technology to tumor typing, metastasis analysis, progression detection, and adjuvant therapy.
    Keywords:  Circulating tumor cells; Research progress; Single-cell sequencing; Tumor heterogeneity
  16. Front Cell Dev Biol. 2021 ;9 708066
      Background: Doxorubicin is one of the most effective chemotherapeutic drugs for breast cancer while its common drug resistance leads to poor patient prognosis and survival. Growing evidence indicate dynamically reorganized chromatin allows rapid access of the gene regulatory machinery to open genomic regions facilitating subsequent gene expression through direct transcription factor (TF) activation and regulatory element binding.Methods: To better understand the regulatory network underlying doxorubicin resistance in breast cancer cells, we explored the systematic alterations of chromatin accessibility and gene expression by the assay for transposase-accessible chromatin using sequencing (ATAC-seq) in combination with RNA sequencing, followed by integrative analysis to identify potential regulators and their targets associated with differentially accessible regions (DARs) in doxorubicin-resistant MCF7 (MCF7-DR) cells.
    Results: A total of 3,963 differentially expressed genes (DEGs) related to doxorubicin resistance were identified, including dramatically up-regulated MT1E, GSTP1, LDHB, significantly down-regulated TFF1, UBB, DSCAM-AS1, and histone-modifying enzyme coding genes HDAC2, EZH2, PRMT5, etc. By integrating with transcriptomic datasets, we identified 18,228 DARs in MCF7-DR cells compared to control, which were positively correlated with their nearest DEGs (r = 0.6). There were 11,686 increased chromatin-accessible regions, which were enriched in up-regulated genes related to diverse KEGG pathways, such as the cell cycle, regulation of actin cytoskeleton, signaling pathways of MAPK, PI3K/Akt and Hippo, which play essential roles in regulating cell apoptosis, proliferation, metabolism, and inflammatory responses. The 6,542 decreased chromatin-accessible regions were identified for the declined doxorubicin-associated biological processes, for instance, endocrine and insulin resistance, central carbon metabolism, signaling pathways of TGF-beta and P53. Combining data from TCGA, analyses of the DAR sequences associated with the DNA-binding motifs of significantly enriched TF families including AP-1, TEAD and FOX, indicated that the loss-function of FOXA1 might play a critical role in doxorubicin-resistant breast cancer cells (DOX-R BCCs).
    Conclusion: These data exhibit the non-genetic landscape of chromatin accessibility and transcript levels in the DOX-R BCCs, and provide clear insights and resources for the detection of critical TFs and potential cis-regulatory elements-based putative therapeutic targets.
    Keywords:  breast cancer; chromatin accessibility; differentially accessible regions; doxorubicin resistance; transcription factor
  17. Methods Mol Biol. 2021 ;2372 11-18
      Mammalian cells express a wide range of transcripts, some protein-coding RNAs (mRNA), and many noncoding (nc) RNAs. Long (l)ncRNAs can modulate protein expression patterns by regulating gene transcription, pre-mRNA splicing, mRNA export, mRNA degradation, protein translation, and protein ubiquitination. Given the growing recognition that lncRNAs have a robust impact upon gene expression, there is rising interest in elucidating the levels and regulation of lncRNAs. A number of high-throughput methods have been developed recently to map the interaction of lncRNAs and RNA-binding proteins (RBPs). However, few of these approaches are suitable for mapping and quantifying RBP-lncRNA interactions. Here, we describe the recently developed method CLIP-qPCR (crosslinking and immunoprecipitation followed by reverse transcription and quantitative PCR) for mapping and quantifying interactions of lncRNAs with canonical and non-canonical RBPs.
    Keywords:  CLIP; RBP; Ribonucleoprotein complexes; lncRNA; qPCR
  18. Curr Opin Cell Biol. 2021 Aug 14. pii: S0955-0674(21)00081-8. [Epub ahead of print]72 116-123
      How cells and tissues migrate from one location to another is a question of significant biological and medical relevance. Migration is generally thought to be controlled by external hardwired guidance cues, which cells follow by polarizing their internal locomotory machinery in the imposed direction. However, a number of recently discovered 'self-guidance' mechanisms have revealed that migrating cells have more control over the path they follow than previously thought. Here, directional information is generated by the migrating cells themselves via a dynamic interplay of cell-intrinsic and -extrinsic regulators. In this review, we discuss how self-guidance can emerge from mechanisms acting at different levels of scale and how these enable cells to rapidly adapt to environmental challenges.
  19. Genome Biol. 2021 Aug 17. 22(1): 229
      BACKGROUND: Liquid-liquid phase separation (LLPS) is an important organizing principle for biomolecular condensation and chromosome compartmentalization. However, while many proteins have been reported to undergo LLPS, quantitative and global analysis of chromatin LLPS property remains absent.RESULTS: Here, by combining chromatin-associated protein pull-down, quantitative proteomics and 1,6-hexanediol (1,6-HD) treatment, we develop Hi-MS and define an anti-1,6-HD index of chromatin-associated proteins (AICAP) to quantify 1,6-HD sensitivity of chromatin-associated proteins under physiological conditions. Compared with known physicochemical properties involved in phase separation, we find that proteins with lower AICAP are associated with higher content of disordered regions, higher hydrophobic residue preference, higher mobility and higher predicted LLPS potential. We also construct BL-Hi-C libraries following 1,6-HD treatment to study the sensitivity of chromatin conformation to 1,6-HD treatment. We find that the active chromatin and high-order structures, as well as the proteins enriched in corresponding regions, are more sensitive to 1,6-HD treatment.
    CONCLUSIONS: Our work provides a global quantitative measurement of LLPS properties of chromatin-associated proteins and higher-order chromatin structure. Hi-MS and AICAP data provide an experimental tool and quantitative resources valuable for future studies of biomolecular condensates.