Bmi-1 regulates the Ink4a/Arf locus to control pancreatic β-cell proliferation

Abstract

The molecular mechanisms that regulate the age- induced increase of p16INK4a expression associated with decreased β-cell proliferation and regeneration are not well understood. We report that in aged islets, de- repression of the Ink4a/Arf locus is associated with decreased Bmi-1 binding, loss of H2A ubiquitylation, increased MLL1 recruitment, and a concomitant increase in H3K4 trimethylation. During β-cell regeneration these histone modifications are reversed resulting in reduced p16 INK4a expression and increased proliferation. We suggest that PcG and TrxG proteins impart a combinatorial code of histone modifications on the Ink4a/Arf locus to control β-cell proliferation during aging and regeneration. © 2009 by Cold Spring Harbor Laboratory Press.