title: Embryonic stem cell-derived hemangioblasts remain epigenetically plastic and require PRC1 to prevent neural gene expression.
abstract: Many lineage-specific developmental regulator genes are transcriptionally primed in embryonic stem (ES) cells; RNA Pol(II) is bound at their promoters but is prevented from productive elongation by the activity of polycomb repressive complexes (PRC) 1 and 2. This epigenetically poised state is thought to enable ES cells to rapidly execute multiple differentiation programs and is recognized by a simultaneous enrichment for trimethylation of lysine 4 and trimethylation of lysine 27 of histone H3 (bivalent chromatin) across promoter regions. Here we show that the chromatin profile of this important cohort of genes is progressively modified as ES cells differentiate toward blood-forming precursors. Surprisingly however, neural specifying genes, such as Nkx2-2, Nkx2-9, and Sox1, remain bivalent and primed even in committed hemangioblasts, as conditional deletion of PRC1 results in overt and inappropriate expression of neural genes in hemangioblasts. These data reinforce the importance of PRC1 for normal hematopoietic differentiation and reveal an unexpected epigenetic plasticity of mesoderm-committed hemangioblasts.
authors.affiliation: Lymphocyte Development Group, Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Luca
authors.initials: L
authors.lastname: Mazzarella
authors.forename: Helle F
authors.initials: HF
authors.lastname: Jørgensen
authors.forename: Jorge
authors.initials: J
authors.lastname: Soza-Ried
authors.forename: Anna V
authors.initials: AV
authors.lastname: Terry
authors.forename: Stella
authors.initials: S
authors.lastname: Pearson
authors.forename: Georges
authors.initials: G
authors.lastname: Lacaud
authors.forename: Valerie
authors.initials: V
authors.lastname: Kouskoff
authors.forename: Matthias
authors.initials: M
authors.lastname: Merkenschlager
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Fisher
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000502:physiology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005326:Fetal Proteins / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D055018:Hemangioblasts / Q000502:physiology*; D006657:Histones / Q000235:genetics; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D063150:Polycomb Repressive Complex 1; D063146:Polycomb-Group Proteins; D012333:RNA, Messenger / Q000235:genetics; D012097:Repressor Proteins / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055748:SOXB1 Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology; D029961:Zebrafish Proteins; D000098908:Brachyury Protein
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D005326:Fetal Proteins; D049452:Green Fluorescent Proteins; D006657:Histones; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D019426:Integrases; D063150:Polycomb Repressive Complex 1; D063146:Polycomb-Group Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D055748:SOXB1 Transcription Factors; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; D040301:Vascular Endothelial Growth Factor Receptor-2; D029961:Zebrafish Proteins; D000098908:Brachyury Protein; C000715627:Nkx2-2 protein, mouse; C112924:Nkx2-9 protein, mouse; C098693:Sox1 protein, mouse; C000715630:nkx2.2b protein, zebrafish; C489840:Ring1 protein, mouse; C489842:Rnf2 protein, mouse; C045073:Cre recombinase