title: A bivalent chromatin structure marks key developmental genes in embryonic stem cells.
abstract: The most highly conserved noncoding elements (HCNEs) in mammalian genomes cluster within regions enriched for genes encoding developmentally important transcription factors (TFs). This suggests that HCNE-rich regions may contain key regulatory controls involved in development. We explored this by examining histone methylation in mouse embryonic stem (ES) cells across 56 large HCNE-rich loci. We identified a specific modification pattern, termed "bivalent domains," consisting of large regions of H3 lysine 27 methylation harboring smaller regions of H3 lysine 4 methylation. Bivalent domains tend to coincide with TF genes expressed at low levels. We propose that bivalent domains silence developmental genes in ES cells while keeping them poised for activation. We also found striking correspondences between genome sequence and histone methylation in ES cells, which become notably weaker in differentiated cells. These results highlight the importance of DNA sequence in defining the initial epigenetic landscape and suggest a novel chromatin-based mechanism for maintaining pluripotency.
authors.affiliation: Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129, USA. bbernstein@partners.org
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Bernstein
authors.forename: Tarjei S
authors.initials: TS
authors.lastname: Mikkelsen
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Xie
authors.forename: Michael
authors.initials: M
authors.lastname: Kamal
authors.forename: Dana J
authors.initials: DJ
authors.lastname: Huebert
authors.forename: James
authors.initials: J
authors.lastname: Cuff
authors.forename: Ben
authors.initials: B
authors.lastname: Fry
authors.forename: Alex
authors.initials: A
authors.lastname: Meissner
authors.forename: Marius
authors.initials: M
authors.lastname: Wernig
authors.forename: Kathrin
authors.initials: K
authors.lastname: Plath
authors.forename: Rudolf
authors.initials: R
authors.lastname: Jaenisch
authors.forename: Alexandre
authors.initials: A
authors.lastname: Wagschal
authors.forename: Robert
authors.initials: R
authors.lastname: Feil
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D002843:Chromatin / Q000737:chemistry* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D000071317:Nanog Homeobox Protein; D009690:Nucleic Acid Conformation; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse