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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 p16 INK4a  and tumor suppressor p19 Arf , 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 p16 INK4a  and p19 Arf . Conditional deletion of β-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 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.

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