Polycomb protein Ezh2 regulates pancreatic β-cell Ink4a/Arf expression and regeneration in diabetes mellitus
| Autor: | Alexander Tarakhovsky, Xueying Gu, Hainan Chen, Seung K. Kim, Rita Bottino, I-hsin Su, Juan L. Contreras |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Aging Streptozocin Histones Mice Histone H3 Insulin-Secreting Cells Diabetes Mellitus Genetics medicine Animals Humans Enhancer of Zeste Homolog 2 Protein neoplasms Cells Cultured Cyclin-Dependent Kinase Inhibitor p16 Cell Proliferation Regulation of gene expression geography Antibiotics Antineoplastic geography.geographical_feature_category biology EZH2 Polycomb Repressive Complex 2 Histone-Lysine N-Methyltransferase Cell cycle Islet Streptozotocin Mice Inbred C57BL Histone Gene Expression Regulation Histone methyltransferase biology.protein Cancer research Female Gene Deletion Research Paper Developmental Biology medicine.drug |
| Zdroj: | Genes & Development. 23:975-985 |
| ISSN: | 1549-5477 0890-9369 |
| DOI: | 10.1101/gad.1742509 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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