Polycomb protein Ezh2 regulates pancreatic β-cell Ink4a/Arf expression and regeneration in diabetes mellitus
- Hainan Chen1,
- Xueying Gu1,
- I-hsin Su2,6,
- Rita Bottino3,
- Juan L. Contreras4,
- Alexander Tarakhovsky2 and
- Seung K. Kim1,5,7
- 1Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA;
- 2Laboratory of Lymphocyte Signaling, The Rockefeller University, New York, New York 10065, USA;
- 3Department of Pediatrics, Division of Immunogenetics, Diabetes Institute, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15213, USA;
- 4Department of Surgery, Division of Transplantation, University of Alabama School of Medicine, Birmingham, Alabama 35294, USA;
- 5Howard Hughes Medical Institute and Department of Medicine, Oncology Division, Stanford University School of Medicine, Stanford, California 94305, USA
Abstract
Proliferation of pancreatic islet β 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 p16INK4a and tumor suppressor p19Arf, limits β-cell regeneration in aging mice, but the basis of β-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 β cells. Ezh2 levels decline in aging islet β cells, and this attrition coincides with reduced histone H3 trimethylation at Ink4a/Arf, and increased levels of p16INK4a and p19Arf. Conditional deletion of β-cell Ezh2 in juvenile mice also reduced H3 trimethylation at the Ink4a/Arf locus, leading to precocious increases of p16INK4a and p19Arf. These mutant mice had reduced β-cell proliferation and mass, hypoinsulinemia, and mild diabetes, phenotypes rescued by germline deletion of Ink4a/Arf. β-Cell destruction with streptozotocin in controls led to increased Ezh2 expression that accompanied adaptive β-cell proliferation and re-establishment of β-cell mass; in contrast, mutant mice treated similarly failed to regenerate β cells, resulting in lethal diabetes. Our discovery of Ezh2-dependent β-cell proliferation revealed unique epigenetic mechanisms underlying normal β-cell expansion and β-cell regenerative failure in diabetes pathogenesis.
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Footnotes
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↵6 Present address: Division of Genomics and Genetics, School of Biological Sciences, Nanyang Technological University, Singapore 639798.
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↵7 Corresponding author.
↵E-MAIL seungkim{at}stanford.edu; FAX (650) 725-7739.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1742509.
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Supplemental material is available at http://www.genesdev.org.
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- Received September 18, 2008.
- Accepted March 13, 2009.
- Copyright © 2009 by Cold Spring Harbor Laboratory Press