The Impact of Epigenetics on Development, Regeneration and Cancer

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (15 April 2021) | Viewed by 21512

Special Issue Editors


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Guest Editor
New York University Abu Dhabi, Abu Dhabi/UAE
Interests: DNA methylation; epigenetic damage; transposons; regeneration; cancer; liver; zebrafish

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Guest Editor
Icahn Sch Med Mt Sinai, Black Family Stem Cell Inst, Dept Cell Dev & Regenerat Biol, New York, NY 10029, USA

Special Issue Information

Dear Colleagues,

The epigenome is implicated in nearly every aspect of cell behavior and identity. Both local and genome-wide alterations to the epigenome contribute to processes as diverse as development and cancer. A combinatorial code of epigenetic modifications regulates gene expression and provides a map for genome organization and nuclear structure. Integration of these regulatory functions of the epigenome is important for forming new cells in embryos and during tissue regeneration. These same features dramatically change in cancer cells. The functional impact of epigenetic modifications and widespread reshaping of the epigenome is critical for development, regeneration, and during carcinogenesis, and, in many cases, the same factors regulate all three of these processes.

This Issue will highlight novel insights regulating developmental and regenerative processes and cover fundamental aspects of epigenetic regulation that contribute to development and cancer. The articles will showcase the range of model systems that have been used to generate our current understanding of the epigenetic impact on development, regeneration, and cancer.

The epigenome has traditionally been studied in the context of cell identity, and in recent years, the role of epigenetic patterns in dictating regenerative capacity, regulating the cell cycle, and suppressing transposable elements during development, regeneration, and cancer have been a focus. There is an emerging understanding of how a combination of epigenetic modifications shape genome organization, and serve as central to the mechanisms by which epigenetic changes contribute to cancer.

Integrated genomics approaches combined with advanced imaging provide a global view of the epigenome in developmental systems, during regeneration and in cancer. This Special Issue will cover recent discoveries that integrate genomics, novel model organisms, and imaging approaches to uncover how the epigenome is patterned in developing and regenerating cells and how this pattern becomes co-opted by cancer cells to advance malignancy. Implications for developing therapeutics that target the epigenome will be reviewed. Reviews and short communications are encouraged.

Prof. Dr. Kirsten Sadler Edepli
Prof. Dr. Elena Ezhkova
Guest Editors

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Keywords

  • epigenetics
  • chromatin
  • stem cells
  • regeneration
  • cancer
  • model organisms

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Published Papers (4 papers)

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Research

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14 pages, 3063 KiB  
Article
Set1 Targets Genes with Essential Identity and Tumor-Suppressing Functions in Planarian Stem Cells
by Prince Verma, Court K. M. Waterbury and Elizabeth M. Duncan
Genes 2021, 12(8), 1182; https://doi.org/10.3390/genes12081182 - 29 Jul 2021
Cited by 4 | Viewed by 2292
Abstract
Tumor suppressor genes (TSGs) are essential for normal cellular function in multicellular organisms, but many TSGs and tumor-suppressing mechanisms remain unknown. Planarian flatworms exhibit particularly robust tumor suppression, yet the specific mechanisms underlying this trait remain unclear. Here, we analyze histone H3 lysine [...] Read more.
Tumor suppressor genes (TSGs) are essential for normal cellular function in multicellular organisms, but many TSGs and tumor-suppressing mechanisms remain unknown. Planarian flatworms exhibit particularly robust tumor suppression, yet the specific mechanisms underlying this trait remain unclear. Here, we analyze histone H3 lysine 4 trimethylation (H3K4me3) signal across the planarian genome to determine if the broad H3K4me3 chromatin signature that marks essential cell identity genes and TSGs in mammalian cells is conserved in this valuable model of in vivo stem cell function. We find that this signature is indeed conserved on the planarian genome and that the lysine methyltransferase Set1 is largely responsible for creating it at both cell identity and putative TSG loci. In addition, we show that depletion of set1 in planarians induces stem cell phenotypes that suggest loss of TSG function, including hyperproliferation and an abnormal DNA damage response (DDR). Importantly, this work establishes that Set1 targets specific gene loci in planarian stem cells and marks them with a conserved chromatin signature. Moreover, our data strongly suggest that Set1 activity at these genes has important functional consequences both during normal homeostasis and in response to genotoxic stress. Full article
(This article belongs to the Special Issue The Impact of Epigenetics on Development, Regeneration and Cancer)
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26 pages, 39029 KiB  
Article
Nuclear Organization during Hepatogenesis in Zebrafish Requires Uhrf1
by Bhavani P. Madakashira, Chi Zhang, Filippo Macchi, Elena Magnani and Kirsten C. Sadler
Genes 2021, 12(7), 1081; https://doi.org/10.3390/genes12071081 - 16 Jul 2021
Cited by 3 | Viewed by 8384
Abstract
Acquisition of cellular fate during development is initiated and maintained by well-coordinated patterns of gene expression that are dictated by the epigenetic landscape and genome organization in the nucleus. While the epigenetic marks that mediate developmental gene expression patterns during organogenesis have been [...] Read more.
Acquisition of cellular fate during development is initiated and maintained by well-coordinated patterns of gene expression that are dictated by the epigenetic landscape and genome organization in the nucleus. While the epigenetic marks that mediate developmental gene expression patterns during organogenesis have been well studied, less is known about how epigenetic marks influence nuclear organization during development. This study examines the relationship between nuclear structure, chromatin accessibility, DNA methylation, and gene expression during hepatic outgrowth in zebrafish larvae. We investigate the relationship between these features using mutants that lack DNA methylation. Hepatocyte nuclear morphology was established coincident with hepatocyte differentiation at 80 h post-fertilization (hpf), and nuclear shape and size continued to change until the conclusion of outgrowth and morphogenesis at 120 hpf. Integrating ATAC-Seq analysis with DNA methylation profiling of zebrafish livers at 120 hpf showed that closed and highly methylated chromatin occupies most transposable elements and that open chromatin correlated with gene expression. DNA hypomethylation, due to mutation of genes encoding ubiquitin-like, containing PHD and RING Finger Domains 1 (uhrf1) and DNA methyltransferase (dnmt1), did not block hepatocyte differentiation, but had dramatic effects on nuclear organization. Hepatocytes in uhrf1 mutants have large, deformed nuclei with multiple nucleoli, downregulation of nucleolar genes, and a complete lack of the nuclear lamina. Loss of lamin B2 staining was phenocopied by dnmt1 mutation. Together, these data show that hepatocyte nuclear morphogenesis coincides with organ morphogenesis and outgrowth, and that DNA methylation directs chromatin organization, and, in turn, hepatocyte nuclear shape and size during liver development. Full article
(This article belongs to the Special Issue The Impact of Epigenetics on Development, Regeneration and Cancer)
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Review

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26 pages, 1286 KiB  
Review
Polycomb Repressive Complex(es) and Their Role in Adult Stem Cells
by Pooja Flora, Gil Dalal, Idan Cohen and Elena Ezhkova
Genes 2021, 12(10), 1485; https://doi.org/10.3390/genes12101485 - 24 Sep 2021
Cited by 13 | Viewed by 4578
Abstract
Populations of resident stem cells (SCs) are responsible for maintaining, repairing, and regenerating adult tissues. In addition to having the capacity to generate all the differentiated cell types of the tissue, adult SCs undergo long periods of quiescence within the niche to maintain [...] Read more.
Populations of resident stem cells (SCs) are responsible for maintaining, repairing, and regenerating adult tissues. In addition to having the capacity to generate all the differentiated cell types of the tissue, adult SCs undergo long periods of quiescence within the niche to maintain themselves. The process of SC renewal and differentiation is tightly regulated for proper tissue regeneration throughout an organisms’ lifetime. Epigenetic regulators, such as the polycomb group (PcG) of proteins have been implicated in modulating gene expression in adult SCs to maintain homeostatic and regenerative balances in adult tissues. In this review, we summarize the recent findings that elucidate the composition and function of the polycomb repressive complex machinery and highlight their role in diverse adult stem cell compartments. Full article
(This article belongs to the Special Issue The Impact of Epigenetics on Development, Regeneration and Cancer)
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16 pages, 1002 KiB  
Review
The METTL3-m6A Epitranscriptome: Dynamic Regulator of Epithelial Development, Differentiation, and Cancer
by Alexandra Maldonado López and Brian C. Capell
Genes 2021, 12(7), 1019; https://doi.org/10.3390/genes12071019 - 30 Jun 2021
Cited by 14 | Viewed by 5274
Abstract
Dynamic modifications on RNA, frequently termed both, “RNA epigenetics” and “epitranscriptomics”, offer one of the most exciting emerging areas of gene regulation and biomedicine. Similar to chromatin-based epigenetic mechanisms, writers, readers, and erasers regulate both the presence and interpretation of these modifications, thereby [...] Read more.
Dynamic modifications on RNA, frequently termed both, “RNA epigenetics” and “epitranscriptomics”, offer one of the most exciting emerging areas of gene regulation and biomedicine. Similar to chromatin-based epigenetic mechanisms, writers, readers, and erasers regulate both the presence and interpretation of these modifications, thereby adding further nuance to the control of gene expression. In particular, the most abundant modification on mRNAs, N6-methyladenosine (m6A), catalyzed by methyltransferase-like 3 (METTL3) has been shown to play a critical role in self-renewing somatic epithelia, fine-tuning the balance between development, differentiation, and cancer, particularly in the case of squamous cell carcinomas (SCCs), which in aggregate, outnumber all other human cancers. Along with the development of targeted inhibitors of epitranscriptomic modulators (e.g., METTL3) now entering clinical trials, the field holds significant promise for treating these abundant cancers. Here, we present the most current summary of this work, while also highlighting the therapeutic potential of these discoveries. Full article
(This article belongs to the Special Issue The Impact of Epigenetics on Development, Regeneration and Cancer)
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