Polycomb protein Ezh2 regulates pancreatic β-cell Ink4a/Arf expression and regeneration in diabetes mellitus

  1. Hainan Chen1,
  2. Xueying Gu1,
  3. I-hsin Su2,6,
  4. Rita Bottino3,
  5. Juan L. Contreras4,
  6. Alexander Tarakhovsky2 and
  7. Seung K. Kim1,5,7
  1. 1Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA;
  2. 2Laboratory of Lymphocyte Signaling, The Rockefeller University, New York, New York 10065, USA;
  3. 3Department of Pediatrics, Division of Immunogenetics, Diabetes Institute, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15213, USA;
  4. 4Department of Surgery, Division of Transplantation, University of Alabama School of Medicine, Birmingham, Alabama 35294, USA;
  5. 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.

    Keywords

    Footnotes

    • 6 Present address: Division of Genomics and Genetics, School of Biological Sciences, Nanyang Technological University, Singapore 639798.

    • 7 Corresponding author.

      E-MAIL seungkim{at}stanford.edu; FAX (650) 725-7739.

    • Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1742509.

    • Supplemental material is available at http://www.genesdev.org.

      • Received September 18, 2008.
      • Accepted March 13, 2009.
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