| Polycomb protein Ezh2 regulates pancreatic beta-cell Ink4a/Arf expression and regeneration in diabetes mellitus. | |
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MedLine Citation:
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PMID: 19390090 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Proliferation of pancreatic islet beta cells is an important mechanism for self-renewal and for adaptive islet expansion. Increased expression of the Ink4a/Arf locus, which encodes the cyclin-dependent kinase inhibitor p16(INK4a) and tumor suppressor p19(Arf), limits beta-cell regeneration in aging mice, but the basis of beta-cell Ink4a/Arf regulation is poorly understood. Here we show that Enhancer of zeste homolog 2 (Ezh2), a histone methyltransferase and component of a Polycomb group (PcG) protein complex, represses Ink4a/Arf in islet beta cells. Ezh2 levels decline in aging islet beta cells, and this attrition coincides with reduced histone H3 trimethylation at Ink4a/Arf, and increased levels of p16(INK4a) and p19(Arf). Conditional deletion of beta-cell Ezh2 in juvenile mice also reduced H3 trimethylation at the Ink4a/Arf locus, leading to precocious increases of p16(INK4a) and p19(Arf). These mutant mice had reduced beta-cell proliferation and mass, hypoinsulinemia, and mild diabetes, phenotypes rescued by germline deletion of Ink4a/Arf. beta-Cell destruction with streptozotocin in controls led to increased Ezh2 expression that accompanied adaptive beta-cell proliferation and re-establishment of beta-cell mass; in contrast, mutant mice treated similarly failed to regenerate beta cells, resulting in lethal diabetes. Our discovery of Ezh2-dependent beta-cell proliferation revealed unique epigenetic mechanisms underlying normal beta-cell expansion and beta-cell regenerative failure in diabetes pathogenesis. |
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Authors:
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Hainan Chen; Xueying Gu; I-hsin Su; Rita Bottino; Juan L Contreras; Alexander Tarakhovsky; Seung K Kim |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Genes & development Volume: 23 ISSN: 1549-5477 ISO Abbreviation: Genes Dev. Publication Date: 2009 Apr |
Date Detail:
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Created Date: 2009-04-24 Completed Date: 2009-04-27 Revised Date: 2010-09-27 |
Medline Journal Info:
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Nlm Unique ID: 8711660 Medline TA: Genes Dev Country: United States |
Other Details:
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Languages: eng Pagination: 975-85 Citation Subset: IM |
Affiliation:
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Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Aging
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metabolism Animals Antibiotics, Antineoplastic / pharmacology Cell Proliferation / drug effects Cells, Cultured Cyclin-Dependent Kinase Inhibitor p16 / genetics, metabolism* Diabetes Mellitus / metabolism* Female Gene Deletion Gene Expression Regulation* / drug effects Histone-Lysine N-Methyltransferase / metabolism* Histones / metabolism Humans Insulin-Secreting Cells / cytology, drug effects, metabolism* Male Mice Mice, Inbred C57BL Streptozocin / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Antibiotics, Antineoplastic; 0/Cdkn2a protein, mouse; 0/Cyclin-Dependent Kinase Inhibitor p16; 0/Histones; 18883-66-4/Streptozocin; EC 2.1.1.-/Ezh2 protein, mouse; EC 2.1.1.43/Histone-Lysine N-Methyltransferase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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