Polycomb and Trithorax Group of Proteins in Development and Disease

A special issue of Epigenomes (ISSN 2075-4655).

Deadline for manuscript submissions: closed (31 May 2018) | Viewed by 50194

Special Issue Editor


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Guest Editor
Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Dr. Aiguader 88, 08003 Barcelona, Spain
Interests: cancer epigenetics; polycomb; chromatin remodeling; gene silencing; cellular differentiation; RNA modifications
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Special Issue Information

Dear Colleagues,

Epigenomes is now accepting submissions for a Special Issue on biological methylation. The Special Issue is Guest-Edited by Dr. Luciano Di Croce from the Centre for Genomic Regulation (CRG) in Barcelona. This Special Issue will include commissioned topical reviews written by leaders in the field. Accepted papers are published online shortly after copy editing. Epigenomes is an open access journal. There are no Article Processing Charges (APCs) for papers submitted in 2017.

Cellular identity and organism development is mediated by two large groups of proteins: The Polycomb group (PcG), which represses transcription, and the Trithorax group (TrxG), which activates transcription. The tight regulation and coordination of both protein families is fundamental to properly coordinate cellular programs that will enable development and differentiation. Deregulation of proteins belonging to PcG or TrxG families leads to a wide spectrum of developmental disorders and diseases, including cancer.

This Special Issue is focused on the function of PcG and TrxG complexes, both in development and disease. We will consider reviews, research, or method manuscripts of exceptional interest on the following topics:

- PcG or TrxG proteins in development of any model organism;
- Role of PcG or TrxG components in disease;
- Role of PcG or TrxG in gene regulation and chromatin architecture.

Dr. Luciano Di Croce
Guest Editor

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Published Papers (7 papers)

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Research

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23 pages, 5553 KiB  
Article
Genetic and Epigenetic Regulation of Zebrafish Intestinal Development
by Bilge San, Marco Aben, Dei M. Elurbe, Kai Voeltzke, Marjo J. Den Broeder, Julien Rougeot, Juliette Legler and Leonie M. Kamminga
Epigenomes 2018, 2(4), 19; https://doi.org/10.3390/epigenomes2040019 - 23 Oct 2018
Cited by 13 | Viewed by 6428
Abstract
Many regulatory pathways are conserved in the zebrafish intestine compared to mammals, rendering it a strong model to study intestinal development. However, the (epi)genetic regulation of zebrafish intestinal development remains largely uncharacterized. We performed RNA-sequencing and chromatin immunoprecipitation (ChIP)-sequencing for activating (H3K4me3) and [...] Read more.
Many regulatory pathways are conserved in the zebrafish intestine compared to mammals, rendering it a strong model to study intestinal development. However, the (epi)genetic regulation of zebrafish intestinal development remains largely uncharacterized. We performed RNA-sequencing and chromatin immunoprecipitation (ChIP)-sequencing for activating (H3K4me3) and repressive (H3K27me3) chromatin marks on isolated intestines at 5, 7, and 9 days post-fertilization (dpf), during which zebrafish transit from yolk dependence to external feeding. RNA-sequencing showed the enrichment of metabolic maintenance genes at all time points and a significant increase in lipid metabolism between 5 and 9 dpf. A strong correlation was observed between gene expression and presence of chromatin marks on gene promoters; H3K4me3-marked genes were expressed higher than H3K27m3-marked genes. Next, we studied a key epigenetic player, Enhancer of zeste homolog 2 (Ezh2). Ezh2 places the repressive H3K27me3 mark on the genome and is highly conserved in vertebrates. We used the nonsense mutant allele ezh2(hu5670) to study the effect of ezh2 loss on intestinal development. These mutants survived gastrulation and died around 11 dpf, showing severe morphological defects in the intestine and liver, accompanied by decreased intestinal (fabp2) and hepatic (fabp10a) marker expressions. Our results suggest that Ezh2 is essential for proper intestinal tissue maintenance and overall survival. Full article
(This article belongs to the Special Issue Polycomb and Trithorax Group of Proteins in Development and Disease)
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19598 KiB  
Article
PRC1 Prevents Replication Stress during Chondrogenic Transit Amplification
by Frank Spaapen, Lars M. T. Eijssen, Michiel E. Adriaens, Tim J. Welting, Peggy Prickaerts, Juliette Salvaing, Vivian E. H. Dahlmans, Donald A. M. Surtel, Frans Kruitz, Roel Kuijer, Yoshihiro Takihara, Hendrik Marks, Hendrik G. Stunnenberg, Bradly G. Wouters, Miguel Vidal and Jan Willem Voncken
Epigenomes 2017, 1(3), 22; https://doi.org/10.3390/epigenomes1030022 - 11 Dec 2017
Viewed by 5740
Abstract
Transit amplification (TA), a state of combined, rapid proliferative expansion and differentiation of stem cell-descendants, remains poorly defined at the molecular level. The Polycomb Repressive Complex 1 (PRC1) protein BMI1 has been localized to TA compartments, yet its exact role in TA is [...] Read more.
Transit amplification (TA), a state of combined, rapid proliferative expansion and differentiation of stem cell-descendants, remains poorly defined at the molecular level. The Polycomb Repressive Complex 1 (PRC1) protein BMI1 has been localized to TA compartments, yet its exact role in TA is unclear. PRC1 proteins control gene expression, cell proliferation and DNA-damage repair. Coordination of such DNA-templated activities during TA is predicted to be crucial to support DNA replication and differentiation-associated transcriptional programming. We here examined whether chondrogenesis provides a relevant biological context for synchronized coordination of these chromatin-based tasks by BMI1. Taking advantage of a prominently featuring TA-phase during chondrogenesis in vitro and in vivo, we here report that TA is completely dependent on intact PRC1 function. BMI1-depleted chondrogenic progenitors rapidly accumulate double strand DNA breaks during DNA replication, present massive non-H3K27me3-directed transcriptional deregulation and fail to undergo chondrogenic TA. Genome-wide accumulation of Topoisomerase 2α and Geminin suggests a model in which PRC1 synchronizes replication and transcription during rapid chondrogenic progenitor expansion. Our combined data reveals for the first time a vital cell-autonomous role for PRC1 during chondrogenesis. We provide evidence that chondrocyte hyper-replication and hypertrophy represent a unique example of programmed senescence in vivo. These findings provide new perspectives on PRC1 function in development and disease. Full article
(This article belongs to the Special Issue Polycomb and Trithorax Group of Proteins in Development and Disease)
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Review

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17 pages, 1985 KiB  
Review
Targeting EZH2 in Multiple Myeloma—Multifaceted Anti-Tumor Activity
by Mohammad Alzrigat, Helena Jernberg-Wiklund and Jonathan D. Licht
Epigenomes 2018, 2(3), 16; https://doi.org/10.3390/epigenomes2030016 - 3 Sep 2018
Cited by 17 | Viewed by 6601
Abstract
The enhancer of zeste homolog 2 (EZH2) is the enzymatic subunit of the polycomb repressive complex 2 (PRC2) that exerts important functions during normal development as well as disease. PRC2 through EZH2 tri-methylates histone H3 lysine tail residue 27 (H3K27me3), a modification associated [...] Read more.
The enhancer of zeste homolog 2 (EZH2) is the enzymatic subunit of the polycomb repressive complex 2 (PRC2) that exerts important functions during normal development as well as disease. PRC2 through EZH2 tri-methylates histone H3 lysine tail residue 27 (H3K27me3), a modification associated with repression of gene expression programs related to stem cell self-renewal, cell cycle, cell differentiation, and cellular transformation. EZH2 is deregulated and subjected to gain of function or loss of function mutations, and hence functions as an oncogene or tumor suppressor gene in a context-dependent manner. The development of highly selective inhibitors against the histone methyltransferase activity of EZH2 has also contributed to insight into the role of EZH2 and PRC2 in tumorigenesis, and their potential as therapeutic targets in cancer. EZH2 can function as an oncogene in multiple myeloma (MM) by repressing tumor suppressor genes that control apoptosis, cell cycle control and adhesion properties. Taken together these findings have raised the possibility that EZH2 inhibitors could be a useful therapeutic modality in MM alone or in combination with other targeted agents in MM. Therefore, we review the current knowledge on the regulation of EZH2 and its biological impact in MM, the anti-myeloma activity of EZH2 inhibitors and their potential as a targeted therapy in MM. Full article
(This article belongs to the Special Issue Polycomb and Trithorax Group of Proteins in Development and Disease)
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51 pages, 3525 KiB  
Review
From Flies to Mice: The Emerging Role of Non-Canonical PRC1 Members in Mammalian Development
by Izabella Bajusz, Gergő Kovács and Melinda K. Pirity
Epigenomes 2018, 2(1), 4; https://doi.org/10.3390/epigenomes2010004 - 5 Feb 2018
Cited by 11 | Viewed by 8563
Abstract
Originally two types of Polycomb Repressive Complexes (PRCs) were described, canonical PRC1 (cPRC1) and PRC2. Recently, a versatile set of complexes were identified and brought up several dilemmas in PRC mediated repression. These new class of complexes were named as non-canonical PRC1s (ncPRC1s). [...] Read more.
Originally two types of Polycomb Repressive Complexes (PRCs) were described, canonical PRC1 (cPRC1) and PRC2. Recently, a versatile set of complexes were identified and brought up several dilemmas in PRC mediated repression. These new class of complexes were named as non-canonical PRC1s (ncPRC1s). Both cPRC1s and ncPRC1s contain Ring finger protein (RING1, RNF2) and Polycomb group ring finger catalytic (PCGF) core, but in ncPRCs, RING and YY1 binding protein (RYBP), or YY1 associated factor 2 (YAF2), replaces the Chromobox (CBX) and Polyhomeotic (PHC) subunits found in cPRC1s. Additionally, ncPRC1 subunits can associate with versatile accessory proteins, which determine their functional specificity. Homozygous null mutations of the ncPRC members in mice are often lethal or cause infertility, which underlines their essential functions in mammalian development. In this review, we summarize the mouse knockout phenotypes of subunits of the six major ncPRCs. We highlight several aspects of their discovery from fly to mice and emerging role in target recognition, embryogenesis and cell-fate decision making. We gathered data from stem cell mediated in vitro differentiation assays and genetically engineered mouse models. Accumulating evidence suggests that ncPRC1s play profound role in mammalian embryogenesis by regulating gene expression during lineage specification of pluripotent stem cells. Full article
(This article belongs to the Special Issue Polycomb and Trithorax Group of Proteins in Development and Disease)
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24 pages, 8141 KiB  
Review
Drosophila DNA-Binding Proteins in Polycomb Repression
by Maksim Erokhin, Pavel Georgiev and Darya Chetverina
Epigenomes 2018, 2(1), 1; https://doi.org/10.3390/epigenomes2010001 - 16 Jan 2018
Cited by 17 | Viewed by 9405
Abstract
The formation of individual gene expression patterns in different cell types is required during differentiation and development of multicellular organisms. Polycomb group (PcG) proteins are key epigenetic regulators responsible for gene repression, and dysregulation of their activities leads to developmental abnormalities and diseases. [...] Read more.
The formation of individual gene expression patterns in different cell types is required during differentiation and development of multicellular organisms. Polycomb group (PcG) proteins are key epigenetic regulators responsible for gene repression, and dysregulation of their activities leads to developmental abnormalities and diseases. PcG proteins were first identified in Drosophila, which still remains the most convenient system for studying PcG-dependent repression. In the Drosophila genome, these proteins bind to DNA regions called Polycomb response elements (PREs). A major role in the recruitment of PcG proteins to PREs is played by DNA-binding factors, several of which have been characterized in detail. However, current knowledge is insufficient for comprehensively describing the mechanism of this process. In this review, we summarize and discuss the available data on the role of DNA-binding proteins in PcG recruitment to chromatin. Full article
(This article belongs to the Special Issue Polycomb and Trithorax Group of Proteins in Development and Disease)
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1378 KiB  
Review
Switch-Like Roles for Polycomb Proteins from Neurodevelopment to Neurodegeneration
by Anke Hoffmann, Vincenza Sportelli, Michael Ziller and Dietmar Spengler
Epigenomes 2017, 1(3), 21; https://doi.org/10.3390/epigenomes1030021 - 1 Dec 2017
Cited by 8 | Viewed by 8496
Abstract
Polycomb Group (PcG) proteins are best-known for maintaining repressive or active chromatin states that are passed on across multiple cell divisions, and thus sustain long-term memory of gene expression. PcG proteins engage different, partly gene- and/or stage-specific, mechanisms to mediate spatiotemporal gene expression [...] Read more.
Polycomb Group (PcG) proteins are best-known for maintaining repressive or active chromatin states that are passed on across multiple cell divisions, and thus sustain long-term memory of gene expression. PcG proteins engage different, partly gene- and/or stage-specific, mechanisms to mediate spatiotemporal gene expression during central nervous system development. In the course of this, PcG proteins bind to various cis-regulatory sequences (e.g., promoters, enhancers or silencers) and coordinate, as well the interactions between distantly separated genomic regions to control chromatin function at different scales ranging from compaction of the linear chromatin to the formation of topological hubs. Recent findings show that PcG proteins are involved in switch-like changes in gene expression states of selected neural genes during the transition from multipotent to differentiating cells, and then to mature neurons. Beyond neurodevelopment, PcG proteins sustain mature neuronal function and viability, and prevent progressive neurodegeneration in mice. In support of this view, neuropathological findings from human neurodegenerative diseases point to altered PcG functions. Overall, improved insight into the multiplicity of PcG functions may advance our understanding of human neurodegenerative diseases and ultimately pave the way to new therapies. Full article
(This article belongs to the Special Issue Polycomb and Trithorax Group of Proteins in Development and Disease)
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1105 KiB  
Review
EZH2 Single Nucleotide Variants (SNVs): Diagnostic and Prognostic Role in 10 Solid Tumor Types
by Elisa Paolicchi, Lorenzo Fornaro, Stefano Landi, Sushilaben Rigas and Francesco Crea
Epigenomes 2017, 1(3), 18; https://doi.org/10.3390/epigenomes1030018 - 6 Nov 2017
Cited by 1 | Viewed by 4047
Abstract
The enhancer of zeste homolog 2 (EZH2) gene encodes a histone methyltransferase that is a catalytic subunit of the Polycomb repressive complex 2 (PRC2) group of proteins that act to repress gene expression. The EZH2 locus is rarely mutated in solid [...] Read more.
The enhancer of zeste homolog 2 (EZH2) gene encodes a histone methyltransferase that is a catalytic subunit of the Polycomb repressive complex 2 (PRC2) group of proteins that act to repress gene expression. The EZH2 locus is rarely mutated in solid tumors and there is no comprehensive study of EZH2 single nucleotide variants (SNVs) associated with cancer susceptibility, prognosis and response to therapy. Here, for the first time, we review the functional roles of EZH2 DNA variants and propose a putative etiological role in 10 various solid tumors including: esophageal, hepatocellular, oral, urothelial, colorectal, lung and gastric cancers. In particular, we found that the C allele of the EZH2 variant rs3757441 is associated with increased EZH2 RNA expression and poorer prognosis (advanced stage) in at least two malignancies such as colorectal and hepatocellular carcinoma. This suggests that the C allele may be a functional risk variant in multiple malignant tumors. We therefore propose that the rs3757441 single nucleotide variant (SNV) be genotyped and real-time PCR assays be performed in large cohort studies in order to confirm this preliminary finding that could be useful for clinical practice. Full article
(This article belongs to the Special Issue Polycomb and Trithorax Group of Proteins in Development and Disease)
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