title: Dynamics of genomic H3K27me3 domains and role of EZH2 during pancreatic endocrine specification.
abstract: Endoderm cells undergo sequential fate choices to generate insulin-secreting beta cells. Ezh2 of the PRC2 complex, which generates H3K27me3, modulates the transition from endoderm to pancreas progenitors, but the role of Ezh2 and H3K27me3 in the next transition to endocrine progenitors is unknown. We isolated endoderm cells, pancreas progenitors, and endocrine progenitors from different staged mouse embryos and analyzed H3K27me3 genome-wide. Unlike the decline in H3K27me3 domains reported during embryonic stem cell differentiation in vitro, we find that H3K27me3 domains increase in number during endocrine progenitor development in vivo. Genes that lose the H3K27me3 mark typically encode transcriptional regulators, including those for pro-endocrine fates, whereas genes that acquire the mark typically are involved in cell biology and morphogenesis. Deletion of Ezh2 at the pancreas progenitor stage enhanced the production of endocrine progenitors and beta cells. Inhibition of EZH2 in embryonic pancreas explants and in human embryonic stem cell cultures increased endocrine progenitors in vitro. Our studies reveal distinct dynamics in H3K27me3 targets in vivo and a means to modulate beta cell development from stem cells.
authors.affiliation: Institute for Regenerative Medicine, Epigenetics Program, Department of Cell and Developmental Biology, Perelman School of Medicine University of Pennsylvania, Philadelphia, PA, USA Ministry of Education Key Laboratory of Cell Proliferation, College of Life Sciences Peking-Tsinghua Center for Life Sciences Peking University, Beijing, China.
authors.forename: Cheng-Ran
authors.initials: CR
authors.lastname: Xu
authors.affiliation: Ministry of Education Key Laboratory of Cell Proliferation, College of Life Sciences Peking-Tsinghua Center for Life Sciences Peking University, Beijing, China.
authors.forename: Lin-Chen
authors.initials: LC
authors.lastname: Li
authors.affiliation: Institute for Regenerative Medicine, Epigenetics Program, Department of Cell and Developmental Biology, Perelman School of Medicine University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Donahue
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Ying
authors.affiliation: Ministry of Education Key Laboratory of Cell Proliferation, College of Life Sciences Peking-Tsinghua Center for Life Sciences Peking University, Beijing, China.
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Gadue
authors.affiliation: Institute for Regenerative Medicine, Epigenetics Program, Department of Cell and Developmental Biology, Perelman School of Medicine University of Pennsylvania, Philadelphia, PA, USA zaret@upenn.edu.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Zaret
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D055098:Endocrine Cells / Q000166:cytology* / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D018507:Gene Expression Regulation, Developmental; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D019426:Integrases / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology* / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D038081:Organogenesis; D063151:Polycomb Repressive Complex 2 / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D006657:Histones; D012333:RNA, Messenger; D056484:Jumonji Domain-Containing Histone Demethylases; C523761:Kdm6b protein, mouse; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2; C045073:Cre recombinase; D019426:Integrases
keywords: Ezh2; H3K27me3; embryogenesis; endocrine; pancreas
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