J Clin Invest. 2013 Nov;123(11):4849-58. doi: 10.1172/JCI69468.
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.
β 细胞功能不足是 1 型和 2 型糖尿病的基础。β 细胞的生长和再生也随着年龄的增长而减少，其机制尚不完全清楚。通过去抑制编码细胞周期蛋白依赖性激酶抑制剂 2a（INK4a）的基因，衰老过程中增强子结合锌指蛋白 2（EZH2）的丧失会阻止成年 β 细胞的复制。我们研究了补充 EZH2 是否可以逆转年龄依赖性的 Ink4a 转录增加。我们生成了一种可诱导的胰腺 β 细胞特异性 Ezh2 转基因小鼠模型，并表明 Ezh2 的转基因表达足以增加年轻成年小鼠的 β 细胞复制和再生。在 8 个月以上的小鼠中，Ezh2 的诱导无法抑制 Ink4a。老年小鼠在 Ink4a 基因座处富集了一个 trithorax 组（TrxG）蛋白复合物。TrxG 复合物成分的敲低，结合 Ezh2 的表达，导致 Ink4a 抑制和老年小鼠 β 细胞的复制增加。这些结果表明，联合调节多梳蛋白（如 EZH2）和 TrxG 蛋白以抑制 Ink4a 可以恢复老年 β 细胞的复制能力。这项研究为扩大成年 β 细胞数量提供了潜在的治疗靶点。
