Combined modulation of polycomb and trithorax genes rejuvenates ß cell replication.
J Clin Invest
; 123(11): 4849-58, 2013 Nov.
Article
em En
| MEDLINE
| ID: mdl-24216481
ABSTRACT
Inadequate functional ß cell mass underlies both type 1 and type 2 diabetes. ß 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 ß 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 ß cell-specific Ezh2 transgenic mouse model and showed that transgene expression of Ezh2 was sufficient to increase ß 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 ß 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 ß cells. This study provides potential therapeutic targets for expansion of adult ß cell mass.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Inibidor p16 de Quinase Dependente de Ciclina
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Células Secretoras de Insulina
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Proteínas do Grupo Polycomb
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Complexo Repressor Polycomb 2
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Clin Invest
Ano de publicação:
2013
Tipo de documento:
Article