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The formation of self-perpetuating protein aggregates such as amyloids is associated with various diseases and provides a basis for transmissible (infectious or heritable) protein isoforms (prions). Many human proteins involved in the regulation of transcription contain potentially amyloidogenic regions. Here, it is shown that short N-terminal isoforms of the human protein PHC3, a component of the chromatin-modifying complex PRC1 (Polycomb repressive complex 1), can form prion-like aggregates in yeast assays, exhibit amyloid properties in the E. coli-based C-DAG assay, and produce detergent-resistant aggregates when ectopically expressed in cultured human cells. Moreover, aggregates of short isoforms can sequester the full-length PHC3 protein, causing its accumulation in the cytosol instead of the nucleus. The introduction of an aggregating short PHC3 isoform alters the transcriptional profile of cultured human cells. It is proposed that the aggregation of short isoforms is involved in the feedback downregulation of PRC1 activity, leading to more open chromatin configuration.

Cancer initiation and progression are typically associated with the accumulation of driver mutations and genomic instability. However, recent studies demonstrated that cancer can also be driven purely by epigenetic alterations, without driver mutations. Specifically, a 24-h transient downregulation of polyhomeotic ( ph -KD), a core component of the Polycomb complex PRC1, is sufficient to induce epigenetically initiated cancers (EICs) in Drosophila , which are proficient in DNA repair and characterized by a stable genome. Whether genomic instability eventually occurs when PRC1 downregulation is performed for extended periods of time remains unclear. Here, we show that prolonged depletion of PH, which mimics cancer initiating events, results in broad dysregulation of DNA replication and repair genes, along with the accumulation of DNA breaks, defective repair, and widespread genomic instability in the cancer tissue. A broad misregulation of H2AK118 ubiquitylation and to a lesser extent of H3K27 trimethylation also occurs and might contribute to these phenotypes. Together, this study supports a model where DNA repair and replication defects accumulate during the tumorigenic transformation epigenetically induced by PRC1 loss, resulting in genomic instability and cancer progression.

Polycomb proteins play an essential role in maintaining the repression of developmental genes in self-renewing embryonic stem cells. The exact mechanism allowing the derepression of polycomb target genes during cell differentiation remains unclear. Our project aimed to identify Cbx8 binding sites in differentiating mouse embryonic stem cells. Therefore, we used a genome-wide chromatin immunoprecipitation of endogenous Cbx8 coupled to direct massive parallel sequencing (ChIP-Seq). Our analysis identified 171 high confidence peaks. By crossing our data with previously published microarray analysis, we show that several differentiation genes transiently recruit Cbx8 during their early activation. Depletion of Cbx8 partially impairs the transcriptional activation of these genes. Both interaction analysis, as well as chromatin immunoprecipitation experiments support the idea that activating Cbx8 acts in the context of an intact PRC1 complex. Prolonged gene activation results in eviction of PRC1 despite persisting H3K27me3 and H2A ubiquitination. The composition of PRC1 is highly modular and changes when embryonic stem cells commit to differentiation. We further demonstrate that the exchange of Cbx7 for Cbx8 is required for the effective activation of differentiation genes. Taken together, our results establish a function for a Cbx8-containing complex in facilitating the transition from a Polycomb-repressed chromatin state to an active state. As this affects several key regulatory differentiation genes this mechanism is likely to contribute to the robust execution of differentiation programs.

Although cancer initiation and progression are generally associated with the accumulation of somatic mutations 1 , 2 , substantial epigenomic alterations underlie many aspects of tumorigenesis and cancer susceptibility 3 – 6 , suggesting that genetic mechanisms might not be the only drivers of malignant transformation 7 . However, whether purely non-genetic mechanisms are sufficient to initiate tumorigenesis irrespective of mutations has been unknown. Here, we show that a transient perturbation of transcriptional silencing mediated by Polycomb group proteins is sufficient to induce an irreversible switch to a cancer cell fate in Drosophila . This is linked to the irreversible derepression of genes that can drive tumorigenesis, including members of the JAK–STAT signalling pathway and zfh1 , the fly homologue of the ZEB1 oncogene, whose aberrant activation is required for Polycomb perturbation-induced tumorigenesis. These data show that a reversible depletion of Polycomb proteins can induce cancer in the absence of driver mutations, suggesting that tumours can emerge through epigenetic dysregulation leading to inheritance of altered cell fates. A transient perturbation of transcriptional silencing mediated by Polycomb proteins is sufficient to induce an epigenetic cancer cell fate in Drosophila in the absence of driver mutations.

The Trithorax group (TrxG) of proteins is a large family of epigenetic regulators that form multiprotein complexes to counteract repressive developmental gene expression programmes established by the Polycomb group of proteins and to promote and maintain an active state of gene expression. Recent studies are providing new insights into how two crucial families of the TrxG — the COMPASS family of histone H3 lysine 4 methyltransferases and the SWI/SNF family of chromatin remodelling complexes — regulate gene expression and developmental programmes, and how misregulation of their activities through genetic abnormalities leads to pathologies such as developmental disorders and malignancies.In this Review, Cenik and Shilatifard focus on two families of Trithorax group proteins: COMPASS histone H3 lysine 4 methyltransferase complexes and SWI/SNF chromatin remodelling complexes. They discuss the roles of these complexes in gene regulation, development and disease.

Triple-negative breast cancer (TNBC) is a collection of biologically diverse cancers characterized by distinct transcriptional patterns, biology, and immune composition. TNBCs subtypes include two basal-like (BL1, BL2), a mesenchymal (M) and a luminal androgen receptor (LAR) subtype. Through a comprehensive analysis of mutation, copy number, transcriptomic, epigenetic, proteomic, and phospho-proteomic patterns we describe the genomic landscape of TNBC subtypes. Mesenchymal subtype tumors display high mutation loads, genomic instability, absence of immune cells, low PD-L1 expression, decreased global DNA methylation, and transcriptional repression of antigen presentation genes. We demonstrate that major histocompatibility complex I (MHC-I) is transcriptionally suppressed by H3K27me3 modifications by the polycomb repressor complex 2 (PRC2). Pharmacological inhibition of PRC2 subunits EZH2 or EED restores MHC-I expression and enhances chemotherapy efficacy in murine tumor models, providing a rationale for using PRC2 inhibitors in PD-L1 negative mesenchymal tumors. Subtype-specific differences in immune cell composition and differential genetic/pharmacological vulnerabilities suggest additional treatment strategies for TNBC. Triple negative breast cancer can be divided into additional subtypes. Here, using omics analyses, the authors show that in the mesenchymal subtype expression of MHC-1 is repressed and that this can be restored by using drugs that target subunits of the epigenetic modifier PRC2.

Recruitment of the Polycomb repressive complexes PRC1 and PRC2 by Xist RNA is an important paradigm for chromatin regulation by long noncoding RNAs. Here, we show that the noncanonical Polycomb group RING finger 3/5 (PCGF3/5)–PRC1 complex initiates recruitment of both PRC1 and PRC2 in response to Xist RNA expression. PCGF3/5–PRC1–mediated ubiquitylation of histone H2A signals recruitment of other noncanonical PRC1 complexes and of PRC2, the latter leading to deposition of histone H3 lysine 27 methylation chromosome-wide. Pcgf3/5 gene knockout results in female-specific embryo lethality and abrogates Xist-mediated gene repression, highlighting a key role for Polycomb in Xist-dependent chromosome silencing. Our findings overturn existing models for Polycomb recruitment by Xist RNA and establish precedence for H2AK119μ1 in initiating Polycomb domain formation in a physiological context.

Polycomb group (PcG) proteins are crucial chromatin regulators that maintain repression of lineage-inappropriate genes and are therefore required for stable cell fate. Recent advances show that PcG proteins form distinct multi-protein complexes in various cellular environments, such as in early development, adult tissue maintenance and cancer. This surprising compositional diversity provides the basis for mechanistic diversity. Understanding this complexity deepens and refines the principles of PcG complex recruitment, target-gene repression and inheritance of memory. We review how the core molecular mechanism of Polycomb complexes operates in diverse developmental settings and propose that context-dependent changes in composition and mechanism are essential for proper epigenetic regulation in development.In this Review, Kim and Kingston discuss the compositional and mechanistic diversity of Polycomb repressive complexes (PRCs) and how their context-dependent formation may be required for proper epigenetic regulation in development.

Polycomb group (PcG) and Trithorax group (TrxG) genes encode important regulators of development and differentiation in metazoans. These two groups of genes were discovered in Drosophila by their opposing effects on homeotic gene (Hox) expression. PcG genes collectively behave as genetic repressors of Hox genes, while the TrxG genes are necessary for HOX gene expression or function. Biochemical studies showed that many PcG proteins are present in two protein complexes, Polycomb repressive complexes 1 and 2, which repress transcription via chromatin modifications. TrxG proteins activate transcription via a variety of mechanisms. Here we summarize the large body of genetic and biochemical experiments in Drosophila on these two important groups of genes.

Histone posttranslational modifications are key regulators of chromatin-associated processes including gene expression, DNA replication and DNA repair. Monoubiquitinated histone H2A, H2Aub (K118 in Drosophila or K119 in vertebrates) is catalyzed by the Polycomb group (PcG) repressive complex 1 (PRC1) and reversed by the PcG-repressive deubiquitinase (PR-DUB)/BAP1 complex. Here we critically assess the current knowledge regarding H2Aub deposition and removal, its crosstalk with PcG repressive complex 2 (PRC2)-mediated histone H3K27 methylation, and the recent attempts toward discovering its readers and solving its enigmatic functions. We also discuss mounting evidence of the involvement of H2A ubiquitination in human pathologies including cancer, while highlighting some knowledge gaps that remain to be addressed. Histone H2A monoubiquitination on lysine 119 in vertebrate and lysine 118 in Drosophila (H2Aub) is an epigenomic mark usually associated with gene repression by Polycomb group factors. Here the authors review the current knowledge on the deposition and removal of H2Aub, its function in transcription and other DNA-associated processes as well as its relevance to human disease.