Maintaining cell identity: PRC2-mediated regulation of transcription and cancer

Comet, Itys; Riising, Eva Madi; Leblanc, Benjamin; Helin, Kristian

doi:10.1038/nrc.2016.83

Cited by 391 publications

(383 citation statements)

References 124 publications

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“…Our finding that PCL proteins specifically recognize unmethylated CpG-motifs through their EH WH domains provides a direct link between CpG islands and PRC2 recruitment. Given that Polycomb-related gene regulation has been implicated in carcinogenesis 1 , our finding may provide a novel target for therapeutic intervention.…”

mentioning

confidence: 91%

“… The Polycomb repressive complex 2 (PRC2) mainly mediates transcriptional repression 1,2 and plays essential roles in various biological processes including the maintenance of cell identity and proper differentiation. Polycomb-like proteins (PCLs), including PHF1, MTF2 and PHF19, are PRC2 associated factors that form sub-complexes with PRC2 core components 3 , and have been proposed to modulate PRC2’s enzymatic activity or its recruitment to specific genomic loci 4–13 .…”

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confidence: 99%

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Polycomb-like proteins link the PRC2 complex to CpG islands

Liefke

Jiang

et al. 2017

Nature

261

323

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The Polycomb repressive complex 2 (PRC2) mainly mediates transcriptional repression1,2 and plays essential roles in various biological processes including the maintenance of cell identity and proper differentiation. Polycomb-like proteins (PCLs), including PHF1, MTF2 and PHF19, are PRC2 associated factors that form sub-complexes with PRC2 core components3, and have been proposed to modulate PRC2’s enzymatic activity or its recruitment to specific genomic loci4–13. Mammalian PRC2 binding sites are enriched in CG content, which correlate with CpG islands that display a low level of DNA methylation14. However, the mechanism of PRC2 recruitment to CpG islands is not fully understood. In this study, we solved the crystal structures of the N-terminal domains of PHF1 and MTF2 with bound CpG-containing DNAs in the presence of H3K36me3-containing histone peptides. We found that the extended homologous (EH) regions of both proteins fold into a winged-helix structure, which specifically binds to the unmethylated CpG motif but in a manner completely different from the canonical winged-helix motif-DNA recognition. We further showed that the PCL EH domains are required for efficient recruitment of PRC2 to CpG island-containing promoters in mouse embryonic cells. Our research provides the first direct evidence demonstrating that PCLs are critical for PRC2 recruitment to CpG islands, thereby further clarifying their roles in transcriptional regulation in vivo.

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mentioning

confidence: 91%

mentioning

confidence: 99%

Polycomb-like proteins link the PRC2 complex to CpG islands

Liefke

Jiang

et al. 2017

Nature

261

323

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“…Mutations in chromatin modifiers are frequent occurrences in a number of cancers and are often associated with aberrant cell fate decisions (1)(2)(3). These lesions are particularly frequent events in non-Hodgkin B-cell Lymphoma.…”

Section: Introductionmentioning

confidence: 99%

EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL

Brach

Johnston-Blackwell

Drew

et al. 2017

Molecular Cancer Therapeutics

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The EZH2 small-molecule inhibitor tazemetostat (EPZ-6438) is currently being evaluated in phase II clinical trials for the treatment of non-Hodgkin lymphoma (NHL). We have previously shown that EZH2 inhibitors display an antiproliferative effect in multiple preclinical models of NHL, and that models bearing gain-of-function mutations in EZH2 were consistently more sensitive to EZH2 inhibition than lymphomas with wild-type (WT) EZH2. Here, we demonstrate that cell lines bearing EZH2 mutations show a cytotoxic response, while cell lines with WT-EZH2 show a cytostatic response and only tumor growth inhibition without regression in a xenograft model. Previous work has demonstrated that cotreatment with tazemetostat and glucocorticoid receptor agonists lead to a synergistic antiproliferative effect in both mutant and wild-type backgrounds, which may provide clues to the mechanism of action of EZH2 inhibition in WT-EZH2 models. Multiple agents that inhibit the B-cell receptor pathway (e.g., ibrutinib) were found to have synergistic benefit when combined with tazemetostat in both mutant and WT-EZH2 backgrounds of diffuse large B-cell lymphomas (DLBCL). The relationship between B-cell activation and EZH2 inhibition is consistent with the proposed role of EZH2 in B-cell maturation. To further support this, we observe that cell lines treated with tazemetostat show an increase in the B-cell maturation regulator, PRDM1/BLIMP1, and gene signatures corresponding to more advanced stages of maturation. These findings suggest that EZH2 inhibition in both mutant and wild-type backgrounds leads to increased Bcell maturation and a greater dependence on B-cell activation signaling.

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“…Overexpression and somatic mutations of EZH2 and other PRC2 subunits have been implicated as oncogenic drivers in multiple cancers, rendering PRC2 an attractive target for the design of new chemotherapeutic drugs (32,33). Multiple groups have reported the development of small molecules that exhibit potent inhibition of EZH2 in vitro and in vivo, with several of these compounds in preclinical studies or clinical trials (recently reviewed in (36)).…”

Section: Structure Of a Prc2/inhibitor Complexmentioning

confidence: 99%

“…Deletion of the genes encoding the PRC2 core subunits in mice results in morphological defects and embryonic lethality, underscoring their importance in regulating epigenetic programs that are essential to development and differentiation (22,30,31). PRC2 has also been shown to have context-dependent roles in cancer (32)(33)(34)(35). Deletions and loss-of-function mutations of PRC2 core subunits have been characterized in certain tumors, whereas overexpression and gain-offunction mutations in EZH2 have been identified in a broad spectrum of cancers, illustrating that PRC2 can exhibit both tumor suppressive and oncogenic activities.…”

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confidence: 99%

Structure, mechanism, and regulation of polycomb-repressive complex 2

Moritz

Trievel

2018

Journal of Biological Chemistry

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Polycomb Repressive Complex 2 (PRC2) methylates lysine 27 in histone H3, a modification associated with epigenetic gene silencing. This complex plays a fundamental role in regulating cellular differentiation and development, and PRC2 overexpression and mutations have been implicated in numerous cancers. In this review, we examine recent studies elucidating the first crystal structures of the PRC2 core complex, yielding seminal insights into its catalytic mechanism, substrate specificity, allosteric regulation, and inhibition by a class of small molecules that are currently undergoing cancer clinical trials. We conclude by exploring unresolved questions and future directions for inquiry regarding PRC2 structure and function.Polycomb group (PcG) proteins represent transcriptional repressors that are present in single cell eukaryotes through multicellular organisms (1,2). The genes encoding many of these proteins were initially characterized in Drosophila as key regulators of epigenetic silencing of homeotic genes (3,4). Subsequent studies demonstrated that PcG proteins function in the context of large heteromeric complexes that repress gene expression within facultative heterochromatin. These PcG complexes include Polycomb Repressive Complexes 1 and 2 (PRC1 and PRC2), as well as the more recently identified Phorepressive Complex (PhoRC) and Polycomb Repressive Deubiquitinase (PR-DUB) (1,5-7). The PRCs possess intrinsic histone modifying activities that contribute to their functions in transcriptional repression. PRC1 monoubiquitinates Lys119 in histone H2A (H2AK119ub1) and can compact chromatin by binding to nucleosomes, whereas PRC2 is a lysine methyltransferase (KMT) that trimethylates Lys27 in histone H3 (H3K27me3), a modification associated with PcG silencing (8-15). PRC1 has been shown to bind H3K27me3, whereas PRC2 can recognize H3K27me3 and H2AK119ub1, facilitating the recruitment of the PRCs to specific genomic loci (16)(17)(18)(19). The interdependence of their enzymatic activities and chromatin localization illustrates how PRC1 and PRC2 can function in concert to epigenetically silence gene expression (20).PRC2 comprises multiple subunits that facilitate its biological functions. The minimal core complex that exhibits methyltransferase activity comprises the core subunits Embryonic Ectoderm Development (EED), Suppressor of Zeste 12 (SUZ12) and the catalytic subunit Enhancer of Zeste Homolog 1 or 2 (EZH1 or EZH2) that possess a conserved catalytic SET domain found in many [21][22][23] (9)(10)(11)20,24,25). Many of these non-core subunits possess intrinsic histone or DNA binding activity and can mediate recruitment of PRC2 to chromatin and promote H3K27 methylation (20,(26)(27)(28)(29). Deletion of the genes encoding the PRC2 core subunits in mice results in morphological defects and embryonic lethality, underscoring their importance in regulating epigenetic programs that are essential to development and differentiation (22,30,31). PRC2 has also been shown to have context-dependent roles in cancer ...

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Maintaining cell identity: PRC2-mediated regulation of transcription and cancer

Cited by 391 publications

References 124 publications

Polycomb-like proteins link the PRC2 complex to CpG islands

Polycomb-like proteins link the PRC2 complex to CpG islands

EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL

Structure, mechanism, and regulation of polycomb-repressive complex 2

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