Combined modulation of polycomb and trithorax genes rejuvenates β cell replication

J Clin Invest. 2013 Nov;123(11):4849-58. doi: 10.1172/JCI69468.

Abstract

Inadequate functional β cell mass underlies both type 1 and type 2 diabetes. β Cell growth and regeneration also decrease with age through mechanisms that are not fully understood. Age-dependent loss of enhancer of zeste homolog 2 (EZH2) prevents adult β cell replication through derepression of the gene encoding cyclin-dependent kinase inhibitor 2a (INK4a). We investigated whether replenishing EZH2 could reverse the age-dependent increase of Ink4a transcription. We generated an inducible pancreatic β cell-specific Ezh2 transgenic mouse model and showed that transgene expression of Ezh2 was sufficient to increase β cell replication and regeneration in young adult mice. In mice older than 8 months, induction of Ezh2 was unable to repress Ink4a. Older mice had an enrichment of a trithorax group (TrxG) protein complex at the Ink4a locus. Knockdown of TrxG complex components, in conjunction with expression of Ezh2, resulted in Ink4a repression and increased replication of β cells in aged mice. These results indicate that combined modulation of polycomb group proteins, such as EZH2, along with TrxG proteins to repress Ink4a can rejuvenate the replication capacity of aged β cells. This study provides potential therapeutic targets for expansion of adult β cell mass.

Publication types

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

MeSH terms

  • Aging / genetics
  • Aging / metabolism
  • Aging / pathology
  • Animals
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • Diabetes Mellitus / genetics
  • Diabetes Mellitus / metabolism
  • Diabetes Mellitus / pathology
  • Enhancer of Zeste Homolog 2 Protein
  • Gene Expression
  • Gene Knockdown Techniques
  • Histone-Lysine N-Methyltransferase / genetics
  • Humans
  • Insulin-Secreting Cells / cytology*
  • Insulin-Secreting Cells / metabolism*
  • Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors
  • Jumonji Domain-Containing Histone Demethylases / genetics
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Transgenic
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Polycomb Repressive Complex 2 / genetics*
  • Polycomb Repressive Complex 2 / metabolism
  • Polycomb-Group Proteins / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism

Substances

  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • Polycomb-Group Proteins
  • RNA, Messenger
  • Myeloid-Lymphoid Leukemia Protein
  • Jumonji Domain-Containing Histone Demethylases
  • Kdm6b protein, mouse
  • Enhancer of Zeste Homolog 2 Protein
  • Ezh2 protein, mouse
  • Histone-Lysine N-Methyltransferase
  • Kmt2a protein, mouse
  • Polycomb Repressive Complex 2