| First Author | Zhou JX | Year | 2013 |
| Journal | J Clin Invest | Volume | 123 |
| Issue | 11 | Pages | 4849-58 |
| PubMed ID | 24216481 | Mgi Jnum | J:204179 |
| Mgi Id | MGI:5529753 | Doi | 10.1172/JCI69468 |
| Citation | Zhou JX, et al. (2013) Combined modulation of polycomb and trithorax genes rejuvenates beta cell replication. J Clin Invest 123(11):4849-58 |
| abstractText | Inadequate functional beta cell mass underlies both type 1 and type 2 diabetes. beta 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 beta 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 beta cell-specific Ezh2 transgenic mouse model and showed that transgene expression of Ezh2 was sufficient to increase beta 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 beta 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 beta cells. This study provides potential therapeutic targets for expansion of adult beta cell mass. |
