PRC2 binds active promoters and contacts nascent RNAs in embryonic stem cells

Kaneko, Syuzo; Son, Jaesung; Shen, Steven S.; Reinberg, Danny; Bonasio, Roberto

doi:10.1038/nsmb.2700

Cited by 294 publications

(336 citation statements)

References 54 publications

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“…Previously proposed models for the recruitment of PRC2 to chromatin by lncRNA, and RNA in general, compared with RNA-independent recruitment mechanisms. (A) Eviction ("Junk Mail Model"): Promiscuous RNA binding to nascent transcripts leads to eviction of PRC2 from highly active genes (Davidovich et al 2013;Kaneko et al 2013) and inhibits its HMTase activity Herzog et al 2014;Kaneko et al 2014b). Simultaneously, H3K4me3 and H3K36me3 active chromatin marks prevent deposition of PRC2 to nucleosomes and inhibit its HMTase activity (Schmitges et al 2011;Yuan et al 2011).…”

Section: Xistmentioning

confidence: 99%

The recruitment of chromatin modifiers by long noncoding RNAs: lessons from PRC2

Davidovich

Cech

2015

RNA

261

224

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Polycomb repressive complex-2 (PRC2) is a histone methyltransferase required for epigenetic silencing during development and cancer. Among chromatin modifying factors shown to be recruited and regulated by long noncoding RNAs (lncRNAs), PRC2 is one of the most studied. Mammalian PRC2 binds thousands of RNAs in vivo, and it is becoming a model system for the recruitment of chromatin modifying factors by RNA. Yet, well-defined PRC2-binding motifs within target RNAs have been elusive. From the protein side, PRC2 RNA-binding subunits contain no known RNA-binding domains, complicating functional studies. Here we provide a critical review of existing models for the recruitment of PRC2 to chromatin by RNAs. This discussion may also serve researchers who are studying the recruitment of other chromatin modifiers by lncRNAs.

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Section: Xistmentioning

confidence: 99%

The recruitment of chromatin modifiers by long noncoding RNAs: lessons from PRC2

Davidovich

Cech

2015

RNA

261

224

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“…In the catalytic lobe, the SRM α-helix of HsPRC2 is shorter than the corresponding helix in CtPRC2, whereas the iSET helix is longer and exhibits a slightly bent conformation in human EZH2 compared to CtPRC2. Furthermore, the Cterminus of the human MCSS motif possesses an additional α-helix that serves as a docking site for nascent RNAs that bind PRC2 and inhibit its activity (65). In contrast, the MCSS motif of CtPRC2 lacks this helix, implying differences in how RNA may modulate the activities of fungal and vertebrate PRC2.…”

Section: Human Prc2 Structurementioning

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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“…However, these findings were based on candidate approaches where only selected RNAs were analyzed (reviewed in [15,[19][20][21]). More recently, unbiased analysis of Ezh2-bound RNA species, however, identified very diverse sets of RNAs including nascent transcripts at transcriptionally active gene loci [51,52]. Surprisingly, the interaction with nascent transcripts does not result in local H3K27 methylation nor in Polycomb mediated gene silencing, suggesting that a nascent transcript may be acting as an inhibitor/evictor for PRC2 or as a decoy for 'functional' RNA-protein interaction.…”

Section: Rna and Histone Modification Binding Can Influence Each Othermentioning

confidence: 99%

RNAs — Physical and functional modulators of chromatin reader proteins

Hiragami-Hamada

Fischle

2014

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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The regulatory role of histone modifications with respect to the structure and function of chromatin is well known. Proteins and protein complexes establishing, erasing and binding these marks have been extensively studied. RNAs have only recently entered the picture of epigenetic regulation with the discovery of a vast number of long non-coding RNAs. Fast growing evidence suggests that such RNAs influence all aspects of histone modification biology. Here, we focus exclusively on the emerging functional interplay between RNAs and proteins that bind histone modifications. We discuss recent findings of reciprocally positive and negative regulations as well as summarize the current insights into the molecular mechanism directing these interactions. This article is part of a Special Issue entitled: Molecular mechanisms of histone modification function.

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PRC2 binds active promoters and contacts nascent RNAs in embryonic stem cells

Cited by 294 publications

References 54 publications

The recruitment of chromatin modifiers by long noncoding RNAs: lessons from PRC2

The recruitment of chromatin modifiers by long noncoding RNAs: lessons from PRC2

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

RNAs — Physical and functional modulators of chromatin reader proteins

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