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

Genes Dev. 2009 Apr 15;23(8):906-11. doi: 10.1101/gad.1742609.


The molecular mechanisms that regulate the age-induced increase of p16(INK4a) expression associated with decreased beta-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 beta-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 beta-cell proliferation during aging and regeneration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging*
  • Animals
  • Cell Line
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Glucose Intolerance / metabolism
  • Insulin-Secreting Cells / cytology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Proteins / metabolism*
  • Polycomb Repressive Complex 1
  • Protein Binding
  • Proto-Oncogene Proteins / metabolism*
  • Repressor Proteins / metabolism*


  • Bmi1 protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • Polycomb Repressive Complex 1