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


Show simple item record Ku, Manching en_US Koche, Richard P. en_US Rheinbay, Esther en_US Mendenhall, Eric M. en_US Endoh, Mitsuhiro en_US Mikkelsen, Tarjei S. en_US Presser, Aviva en_US Nusbaum, Chad en_US Xie, Xiaohui en_US Chi, Andrew S. en_US Adli, Mazhar en_US Kasif, Simon en_US Ptaszek, Leon M. en_US Cowan, Chad A. en_US Lander, Eric S. en_US Koseki, Haruhiko en_US Bernstein, Bradley E. en_US 2012-01-11T00:42:05Z 2012-01-11T00:42:05Z 2008-10-31 en_US
dc.identifier.citation Ku, Manching, Richard P. Koche, Esther Rheinbay, Eric M. Mendenhall, Mitsuhiro Endoh, Tarjei S. Mikkelsen, Aviva Presser, Chad Nusbaum, Xiaohui Xie, Andrew S. Chi, Mazhar Adli, Simon Kasif, Leon M. Ptaszek, Chad A. Cowan, Eric S. Lander, Haruhiko Koseki, Bradley E. Bernstein. "Genomewide Analysis of PRC1 and PRC2 Occupancy Identifies Two Classes of Bivalent Domains" PLoS Genetics 4(10): e1000242. (2008) en_US
dc.identifier.issn 1553-7404 en_US
dc.description.abstract In embryonic stem (ES) cells, bivalent chromatin domains with overlapping repressive (H3 lysine 27 tri-methylation) and activating (H3 lysine 4 tri-methylation) histone modifications mark the promoters of more than 2,000 genes. To gain insight into the structure and function of bivalent domains, we mapped key histone modifications and subunits of Polycomb-repressive complexes 1 and 2 (PRC1 and PRC2) genomewide in human and mouse ES cells by chromatin immunoprecipitation, followed by ultra high-throughput sequencing. We find that bivalent domains can be segregated into two classes—the first occupied by both PRC2 and PRC1 (PRC1-positive) and the second specifically bound by PRC2 (PRC2-only). PRC1-positive bivalent domains appear functionally distinct as they more efficiently retain lysine 27 tri-methylation upon differentiation, show stringent conservation of chromatin state, and associate with an overwhelming number of developmental regulator gene promoters. We also used computational genomics to search for sequence determinants of Polycomb binding. This analysis revealed that the genomewide locations of PRC2 and PRC1 can be largely predicted from the locations, sizes, and underlying motif contents of CpG islands. We propose that large CpG islands depleted of activating motifs confer epigenetic memory by recruiting the full repertoire of Polycomb complexes in pluripotent cells. Author Summary Polycomb-group (PcG) proteins play essential roles in the epigenetic regulation of gene expression during development. PcG proteins are repressors that catalyze lysine 27 tri-methylation on histone H3. They are antagonized by trithorax-group proteins that catalyze lysine 4 tri-methylation. Recent studies of ES cells revealed a novel chromatin pattern consisting of overlapping lysine 27 and lysine 4 tri-methylation. Genomic regions with these opposing modifications were termed "bivalent domains" and proposed to silence developmental regulators while keeping them "poised" for alternate fates. However, our understanding of PcG regulation and bivalent domains remains limited. For instance, bivalent domains affect over 2,000 promoters with diverse functions, which suggests that they may function in diverse cellular processes. Moreover, the mechanisms that underlie the targeting of PcG complexes to specific genomic regions remain completely unknown. To gain insight into these issues, we used ultra high-throughput sequencing to map PcG complexes and related modifications genomewide in human and mouse ES cells. The data identify two classes of bivalent domains with distinct regulatory properties. They also reveal striking relationships between genome sequence and chromatin state that suggest a prominent role for the DNA sequence in dictating the genomewide localization of PcG complexes and, consequently, bivalent domains in ES cells. en_US
dc.description.sponsorship Croucher Foundation; National Human Genome Research Institute; National Institutes of Health (R01 HG003367-01A1); National Cancer Institute; Genome Network Project; Human Genome Research Institute; the Burroughs Wellcome Fund; the Culpeper Foundation; Harvard Stem Cell Institute; Massachusetts General Hospital; Broad Institute of Harvard and MIT en_US
dc.language.iso en en_US
dc.publisher Public Library of Science en_US
dc.title Genomewide Analysis of PRC1 and PRC2 Occupancy Identifies Two Classes of Bivalent Domains en_US
dc.type article en_US
dc.identifier.doi 10.1371/journal.pgen.1000242 en_US
dc.identifier.pubmedid 18974828 en_US
dc.identifier.pmcid 2567431 en_US

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