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

Sangeeta Dhawan; Shuen-Ing Tschen; Anil Bhushan

doi:10.1101/gad.1742609

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

¹Larry L. Hillblom Islet Research Center, Department of Medicine, University of California at Los Angeles, Los Angeles, California 90024, USA;
²Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California 90024, USA

Abstract

The molecular mechanisms that regulate the age-induced increase of p16^INK4a expression associated with decreased β-cell proliferation and regeneration are not well understood. We report that in aged islets, derepression 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.

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Footnotes

↵3 Corresponding author.

↵E-MAIL abhushan{at}mednet.ucla.edu; FAX (310) 206-5368.
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1742609.
Supplemental material is available at http://www.genesdev.org.
- Received September 18, 2008.
- Accepted March 6, 2009.