Tudor domains of the PRC2 components PHF1 and PHF19 selectively bind to histone H3K36me3

Su, Qin; Guo, Yahong; Xu, Chao; Bian, Chuanbing; Fu, Minfei; Gong, Sarah; Min, Jinrong

doi:10.1016/j.bbrc.2012.11.116

Cited by 50 publications

(40 citation statements)

References 49 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

251

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

251

323

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“…In mammals, there are three PCL orthologues: Pcl1, Pcl2/Mtf2, and Pcl3/Phf19 (66). Consistent with the fly phenotype, Phf19 facilitates PRC2 recruitment to chromatin and therefore H3K27me3 deposition (98)(99)(100). Surprisingly, although Mtf2 knockdown ESCs contain increased global levels of H3K27me3, PRC2 recruitment and H3K27me3 levels are reduced at some PRC2 target genes (101).…”

Section: Do These Complexes Have Redundant Functions In Escs?mentioning

confidence: 80%

“…Pcl proteins contain a Tudor domain, which recognizes H3K36me3 (98-100). Mechanistically, Phf19 recruits the H3K36me3 demethylases NO66 and Kdm2b to active genes through its binding to H3K36me3, thus favoring PRC2 recruitment and resulting in gene repression (98)(99)(100). More recently, C17orf96 was identified as a new PRC2-associated protein in a complex also containing Jarid2 and Pcl2.…”

Section: Do These Complexes Have Redundant Functions In Escs?mentioning

confidence: 99%

Pluripotency and Epigenetic Factors in Mouse Embryonic Stem Cell Fate Regulation

Morey

Santanach

Croce

2015

Molecular and Cellular Biology

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c Embryonic stem cells (ESCs) are characterized by their ability to self-renew and to differentiate into all cell types of a given organism. Understanding the molecular mechanisms that govern the ESC state is of great interest not only for basic research-for instance, ESCs represent a perfect system to study cellular differentiation in vitro-but also for their potential implications in human health, as these mechanisms are likewise involved in cancer progression and could be exploited in regenerative medicine. In this minireview, we focus on the latest insights into the molecular mechanisms mediated by the pluripotency factors as well as their roles during differentiation. We also discuss recent advances in understanding the function of the epigenetic regulators, Polycomb and MLL complexes, in ESC biology. Within 2 days after fertilization, a mouse oocyte has undergone a series of cellular divisions and has developed into the morula embryo. The totipotent cells within the morula then divide and further specialize to form the hollow blastocyst sphere. The outer layer of the blastocyst contains the trophectoderm cells, while the inner cell mass (ICM) contains the pluripotent embryonic stem cells (ESCs) that will give rise in the developing embryo to all cell types of the three germ layers-ectoderm, mesoderm, and endoderm. Mouse ESCs were first isolated by Evans and Kaufman in 1981 (1) and have since been extensively studied. Under proper cell culture conditions, ESCs can divide and self-renew indefinitely, yet under differentiation stimuli, ESCs can also differentiate into virtually all cell types of the organism.Which molecular mechanisms control the decision of ESCs to self-renew or to differentiate? During the last decades, several transcription factors have been identified to be essential for ESC pluripotency. These transcription factors regulate pluripotency by a so-called "pluripotency network" that regulates their own expression and coregulates the expression of other key transcription factors through multiple mechanisms. Interestingly, pluripotency is controlled at the transcriptional levels of genes through specific signaling pathways and epigenetic factors.Epigenetics is the study of heritable changes in gene expression that are not caused by changes at the DNA sequence level. The Polycomb and MLL (myeloid-lineage leukemia) complexes are two of the best-characterized epigenetic machineries implicated in ESC pluripotency and differentiation. Although pluripotency factors do not physically interact with Polycomb and MLL complexes, they coregulate lineage-specific genes important for ESC differentiation.In this review, we discuss the most recent advances in understanding mouse ESC pluripotency and differentiation, paying particular attention to Oct4, Nanog, and Sox2, as well as to factors involved in the exit from pluripotency. Finally, we discuss the function and the molecular mechanisms of the Polycomb and MLL complexes in mouse ESC pluripotency. MASTER REGULATORS OF ESC IDENTITY: THE Oct4, Sox2, AND Nano...

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“…17 The Tudor domains of PHF1 and PHF19 have recently been found to recognize trimethylated lysine 36 of histone H3 (H3K36me3). 12,[14][15][16]18 The PHF1-H3K36me3 interaction impedes the enzymatic activity of PRC2 and is important for the retention of PHF1 at the sites of DNA damage. 12 Binding of PHF19 to H3K36me3 recruits PRC2 and NO66 to embryonic stem cell genes during differentiation and is required for the full enzymatic activity of PRC2 and repression of a subset of PRC2 target genes.…”

Section: Introductionmentioning

confidence: 99%

An aromatic cage is required but not sufficient for binding of Tudor domains of the Polycomblike protein family to H3K36me3

et al. 2015

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Polycomblike (Pcl) proteins are important transcriptional regulators and components of the Polycomb Repressive Complex 2 (PRC2). The Tudor domains of human homologs PHF1 and PHF19 have been found to recognize trimethylated lysine 36 of histone H3 (H3K36me3); however, the biological role of Tudor domains of other Pcl proteins remains poorly understood. Here, we characterize the molecular basis underlying histone binding activities of the Tudor domains of the Pcl family. In contrast to a predominant view, we found that the methyl lysine-binding aromatic cage is necessary but not sufficient for recognition of H3K36me3 by these Tudor domains and that a hydrophobic patch, adjacent to the aromatic cage, is also required.

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Tudor domains of the PRC2 components PHF1 and PHF19 selectively bind to histone H3K36me3

Cited by 50 publications

References 49 publications

Polycomb-like proteins link the PRC2 complex to CpG islands

Polycomb-like proteins link the PRC2 complex to CpG islands

Pluripotency and Epigenetic Factors in Mouse Embryonic Stem Cell Fate Regulation

An aromatic cage is required but not sufficient for binding of Tudor domains of the Polycomblike protein family to H3K36me3

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