Genomewide Analysis of PRC1 and PRC2 Occupancy Identifies Two Classes of Bivalent Domains

Ku, Manching; Koche, Richard P.; Rheinbay, Esther; Mendenhall, Eric M.; Endoh, Mitsuhiro; Mikkelsen, Tarjei S.; Presser, Aviva; Nusbaum, Chad; Xie, Xiaohui; Andrew, S.; Adli, Mazhar; Kasif, Simon; Ptaszek, Leon M.; Cowan, Chad A.; Lander, Eric S.; Koseki, Haruhiko; Bernstein, B

doi:10.1371/journal.pgen.1000242

Cited by 905 publications

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“…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 . Mammalian PRC2 binding sites are enriched in CG content, which correlate with CpG islands that display a low level of DNA methylation 14 . However, the mechanism of PRC2 recruitment to CpG islands is not fully understood.…”

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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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confidence: 99%

“…3f, g, h). PRC2 and its associated PCL proteins are commonly located at CpG islands 14 . 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.…”

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confidence: 99%

Polycomb-like proteins link the PRC2 complex to CpG islands

Liefke

Jiang

et al. 2017

Nature

261

323

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“…PRC2 might also associate with CG-rich sequences in genes devoid of DNA motifs for transcriptional activators in ES cells. 50 We found that SUZ12 and EZH2 interact with Spi-1 and bind to the Bim promoter at the H3K27me3 sites that are 0.9 kb distant from the Spi-1 binding motif. As both Spi-1 and PRC2 are required to favour H3K27m3 at the Bim promoter, at least, two scenarios might fit with these findings (Figure 7f).…”

Section: α-Suz12mentioning

confidence: 72%

Epigenetic silencing of Bim transcription by Spi-1/PU.1 promotes apoptosis resistance in leukaemia

et al. 2013

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Deregulation of transcriptional networks contributes to haematopoietic malignancies. The transcription factor Spi-1/PU.1 is a master regulator of haematopoiesis and its alteration leads to leukaemia. Spi-1 overexpression inhibits differentiation and promotes resistance to apoptosis in erythroleukaemia. Here, we show that Spi-1 inhibits mitochondrial apoptosis in vitro and in vivo through the transcriptional repression of Bim, a proapoptotic factor. BIM interacts with MCL-1 that behaves as a major player in the survival of the preleukaemic cells. The repression of BIM expression reduces the amount of BIM-MCL-1 complexes, thus increasing the fraction of potentially active antiapoptotic MCL-1. We then demonstrate that Spi-1 represses Bim transcription by binding to the Bim promoter and by promoting the trimethylation of histone 3 on lysine 27 (H3K27me3, a repressive histone mark) on the Bim promoter. The PRC2 repressive complex of Polycomb is directly responsible for the deposit of H3K27me3 mark at the Bim promoter. SUZ12 and the histone methyltransferase EZH2, two PRC2 subunits bind to the Bim promoter at the same location than H3K27me3, distinct of the Spi-1 DNA binding site. As Spi-1 interacts with SUZ12 and EZH2, these results indicate that Spi-1 modulates the activity of PRC2 without directly recruiting the complex to the site of its activity on the chromatin. Our results identify a new mechanism whereby Spi-1 represses transcription and provide mechanistic insights on the antiapoptotic function of a transcription factor mediated by the epigenetic control of gene expression. Cell Death and Differentiation (2013) 20, 1268-1278; doi:10.1038/cdd.2013.88; published online 12 July 2013Acute myeloid leukaemia (AML) develops through a multistep process driven by the progressive accumulation of mutations, leading to deregulation of cell proliferation and differentiation. Most frequently, abnormalities in cell differentiation are the result of loss-of-function mutations in lineage-specific transcription factors, whereas alterations in cell proliferation are associated with gain-of-function mutations in signalling pathways. 1 Mutations that target components of the spliceosomal machinery 2 and epigenetic regulators 3 have been identified as well, although their functional consequences in leukaemogenesis are not clear. To date, AML treatments are largely determined by the nature of the identified mutated proteins and a major challenge is to design molecules that can target each molecular alteration contributing to transformation. For that, understanding the molecular mechanisms controlled by an oncoprotein is one essential step. We have previously described a mouse model of erythroleukaemia (Spi-1 transgenic mice) that recapitulates the multistep development of human AML. 4 Spi-1 is a master transcription factor of haematopoiesis that is also involved in pre-mRNA splicing regulation. 5 During the preleukaemic stage of the disease, the differentiation blockage of the erythroid progenitors is the first oncogenic mark assoc...

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“…In addition, some enzymes, e.g. MLL1, KDM2A, PRC2 have higher binding affinity at some DNA sequence elements, e.g., CpG islands (38)(39)(40)(41). To reflect these observations, we follow the treatment of Angel et al (10), and Hodge and Crabtree (11), to denote a "nucleation region" for a small number of nucleosomes, on which the enzymes have higher binding affinity compared to the nonspecific background binding affinity on other nucleosomes.…”

Section: Insert Figurementioning

confidence: 99%

Computational Modeling to Elucidate Molecular Mechanisms of Epigenetic Memory

Xing

Jin

Zhang

et al. 2015

Epigenetic Technological Applications

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(100-250 words)How do mammalian cells that share the same genome exist in notably distinct phenotypes, exhibiting differences in morphology, gene expression patterns, and epigenetic chromatin statuses? Furthermore how do cells of different phenotypes differentiate reproducibly from a single fertilized egg? These are fundamental problems in developmental biology. Epigenetic histone modifications play an important role in the maintenance of different cell phenotypes. The exact molecular mechanism for inheritance of the modification patterns over cell generations remains elusive. The complexity comes partly from the number of molecular species and the broad time scales involved. In recent years mathematical modeling has made significant contributions on elucidating the molecular mechanisms of DNA methylation and histone Book chapter in Epigenetic Technological Applications (Elsevier), in press 2 covalent modification inheritance. We will pedagogically introduce the typical procedure and some technical details of performing a mathematical modeling study, and discuss future developments. Keywords (5-10)Histone epigenetic memory, mathematical modeling, reader and writer, pattern reconstruction, stochastic dynamics, histone modification enzyme, post-translational modification Outline:In this chapter we discuss how to use mathematical modeling to explore the dynamics and mechanism of histone modification dynamics. Book chapter inEpigenetic Technological Applications (Elsevier), in press 3 Textbody

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Genomewide Analysis of PRC1 and PRC2 Occupancy Identifies Two Classes of Bivalent Domains

Cited by 905 publications

References 66 publications

Polycomb-like proteins link the PRC2 complex to CpG islands

Polycomb-like proteins link the PRC2 complex to CpG islands

Epigenetic silencing of Bim transcription by Spi-1/PU.1 promotes apoptosis resistance in leukaemia

Computational Modeling to Elucidate Molecular Mechanisms of Epigenetic Memory

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