Document Detail


Polycomb protein Ezh2 regulates pancreatic beta-cell Ink4a/Arf expression and regeneration in diabetes mellitus.
MedLine Citation:
PMID:  19390090     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Hainan Chen; Xueying Gu; I-hsin Su; Rita Bottino; Juan L Contreras; Alexander Tarakhovsky; Seung K Kim
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Genes & development     Volume:  23     ISSN:  1549-5477     ISO Abbreviation:  Genes Dev.     Publication Date:  2009 Apr 
Date Detail:
Created Date:  2009-04-24     Completed Date:  2009-04-27     Revised Date:  2013-06-02    
Medline Journal Info:
Nlm Unique ID:  8711660     Medline TA:  Genes Dev     Country:  United States    
Other Details:
Languages:  eng     Pagination:  975-85     Citation Subset:  IM    
Affiliation:
Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
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MeSH Terms
Descriptor/Qualifier:
Aging / 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
Polycomb Repressive Complex 2
Streptozocin / pharmacology
Chemical
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/Cdkn2a protein, mouse; 0/Cyclin-Dependent Kinase Inhibitor p16; 0/Histones; 18883-66-4/Streptozocin; EC 2.1.1.43/Ezh2 protein, mouse; EC 2.1.1.43/Histone-Lysine N-Methyltransferase; EC 2.1.1.43/Polycomb Repressive Complex 2
Comments/Corrections

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