An H3K36 Methylation-Engaging Tudor Motif of Polycomb-like Proteins Mediates PRC2 Complex Targeting

Cai, Ling; Rothbart, Scott B.; Lu, Rui; Xu, Bowen; Chen, Wei Yi; Tripathy, Ashutosh; Rockowitz, Shira; Zheng, Deyou; Patel, Dinshaw J.; Allis, C. David; Strahl, Brian D.; Song, Jikui; Wang, Gang Greg

doi:10.1016/j.molcel.2012.11.026

Cited by 217 publications

(230 citation statements)

References 39 publications

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“…3a, b), similar to the results from isolated Tudor domains 4,6,7,11,15,16 , suggesting that the presence of the other domains does not interfere with the histone binding preference. In addition, we confirmed that the Tudor domains rather than the PHD1/2 fingers are responsible for the above recognition, as mutation of an aromatic-cage residue in the Tudor domain (Y47A for PHF1, Y62A for MTF2) led to a complete loss in binding affinity (Extended Data Table 2).…”

supporting

confidence: 81%

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Polycomb-like proteins link the PRC2 complex to CpG islands

Liefke

Jiang

et al. 2017

Nature

247

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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supporting

confidence: 81%

“…1a). Currently, only the structures of the isolated Tudor domains of PCLs have been solved, which bind preferentially to histone H3 trimethylated at lysine 36 (H3K36me3) 4,6,7,11,15,16 . We solved the crystal structure of the PHF1 Tudor-PHD1-PHD2-EH cassette at 1.9 Å resolution (Extended Data Table 1).…”

mentioning

confidence: 99%

Polycomb-like proteins link the PRC2 complex to CpG islands

Liefke

Jiang

et al. 2017

Nature

247

323

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“…57 However, Polycomb proteins can also facilitate productive gene expression required for establishing the identity and for differentiation of stem cells, 42,58 reviewed in 59 . This activation is accompanied by replacement of H327me3 by H3K27ac 41 and increasing levels of H2az, H3K4me1, and RNA Polymerase II transcription.…”

Section: Discussionmentioning

confidence: 99%

Polycomb repressive complex 2 epigenomic signature defines age-associated hypermethylation and gene expression changes

Dozmorov

2015

Epigenetics

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Although age-associated gene expression and methylation changes have been reported throughout the literature, the unifying epigenomic principles of aging remain poorly understood. Recent explosion in availability and resolution of functional/regulatory genome annotation data (epigenomic data), such as that provided by the ENCODE and Roadmap Epigenomics projects, provides an opportunity for the identification of epigenomic mechanisms potentially altered by age-associated differentially methylated regions (aDMRs) and regulatory signatures in the promoters of ageassociated genes (aGENs). In this study we found that aDMRs and aGENs identified in multiple independent studies share a common Polycomb Repressive Complex 2 signature marked by EZH2, SUZ12, CTCF binding sites, repressive H3K27me3, and activating H3K4me1 histone modification marks, and a "poised promoter" chromatin state. This signature is depleted in RNA Polymerase II-associated transcription factor binding sites, activating H3K79me2, H3K36me3, H3K27ac marks, and an "active promoter" chromatin state. The PRC2 signature was shown to be generally stable across cell types. When considering the directionality of methylation changes, we found the PRC2 signature to be associated with aDMRs hypermethylated with age, while hypomethylated aDMRs were associated with enhancers. In contrast, aGENs were associated with the PRC2 signature independently of the directionality of gene expression changes. In this study we demonstrate that the PRC2 signature is the common epigenomic context of genomic regions associated with hypermethylation and gene expression changes in aging.

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“…It adds weight to the expectation that we will also find physical coupling of the opposite combination of activities, histone deactivation and repression, which are effectively coordinated in many systems (3,4,6,45). Identification of the H3K36me3 demethylase at FLC will allow its physical association with PRC2 to be investigated.…”

Section: Elf6 and Jumonji Domain-containing Protein 13 Are Partiallymentioning

confidence: 99%

“…Transcriptional states are induced by internal developmental signals or triggered by environmental conditions and are then epigenetically maintained through many cell divisions. Considerable evidence suggests that opposing histone modifications mark different transcriptional states (1)(2)(3)(4)(5)(6). However, there is still great debate as to how histone-based transcriptional states are initially established and maintained through development (7,8).…”

mentioning

confidence: 99%

Physical coupling of activation and derepression activities to maintain an active transcriptional state at FLC

Yang

Howard

Dean

2016

Proc. Natl. Acad. Sci. U.S.A.

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Establishment and maintenance of gene expression states is central to development and differentiation. Transcriptional and epigenetic mechanisms interconnect in poorly understood ways to determine these states. We explore these mechanisms through dissection of the regulation of Arabidopsis thaliana FLOWERING LOCUS C (FLC). FLC can be present in a transcriptionally active state marked by H3K36me3 or a silent state marked by H3K27me3. Here, we investigate the trans factors modifying these opposing histone states and find a physical coupling in vivo between the H3K36 methyltransferase, SDG8, and the H3K27me3 demethylase, ELF6. Previous modeling has predicted this coupling would exist as it facilitates bistability of opposing histone states. We also find association of SDG8 with the transcription machinery, namely RNA polymerase II and the PAF1 complex. Delivery of the active histone modifications is therefore likely to be through transcription at the locus. SDG8 and ELF6 were found to influence the localization of each other on FLC chromatin, showing the functional importance of the interaction. In addition, both influenced accumulation of the associated H3K27me3 and H3K36me3 histone modifications at FLC. We propose the physical coupling of activation and derepression activities coordinates transcriptional activity and prevents ectopic silencing.epigenetic regulation | histone modifications | histone methyltransferase | histone demethylase | FLOWERING LOCUS C C hromatin-based transcriptional activity is particularly important in multicellular organisms, where cells differentiate into very different developmental states. Transcriptional states are induced by internal developmental signals or triggered by environmental conditions and are then epigenetically maintained through many cell divisions. Considerable evidence suggests that opposing histone modifications mark different transcriptional states (1-6). However, there is still great debate as to how histone-based transcriptional states are initially established and maintained through development (7,8). We used Arabidopsis FLOWERING LOCUS C (FLC) as a model gene to explore histone-based transcriptional regulation and epigenetic memory. Local chromatin states are critical for quantitatively controlling FLC expression (9). Active FLC expression requires functional FRIGIDA (FRI) and a set of histone modifying Trithorax homologs, Complex Proteins Associated with Set1 (COMPASS), RNA polymerase II Associated Factor 1 complex (PAF1C), and SET DOMAIN GROUP 8 (SDG8), the major H3K36 methyltransferase (10-17). Repression of FLC requires either the autonomous pathway, which coordinately influences transcriptional initiation and elongation with associated chromatin modulation, or vernalization, the cold-induced Polycomb silencing (18-21). Both of these involve accumulation of high levels of H3K27me3 at FLC (20-22). A series of FLC antisense transcripts (COOLAIR) contribute to these repression pathways (18,(23)(24)(25)(26) Opposing H3K36me3 and H3K27me3 states are particularly ...

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An H3K36 Methylation-Engaging Tudor Motif of Polycomb-like Proteins Mediates PRC2 Complex Targeting

Cited by 217 publications

References 39 publications

Polycomb-like proteins link the PRC2 complex to CpG islands

Polycomb-like proteins link the PRC2 complex to CpG islands

Polycomb repressive complex 2 epigenomic signature defines age-associated hypermethylation and gene expression changes

Physical coupling of activation and derepression activities to maintain an active transcriptional state at FLC

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