Aging-Dependent Demethylation of Regulatory Elements Correlates with Chromatin State and Improved β Cell Function.
Aging-Dependent Demethylation of Regulatory Elements Correlates with Chromatin State and Improved β Cell Function.
复制标题
衰老依赖性调节元件去甲基化与染色质状态和改善的 β 细胞功能相关。
DOI：
10.1016/j.cmet.2015.07.025
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发表时间：
2015-10-06
期刊：
影响因子：
29
通讯作者：
Kaestner KH
中科院分区：
文献类型：
--
作者：
Avrahami D;Li C;Zhang J;Schug J;Avrahami R;Rao S;Stadler MB;Burger L;Schübeler D;Glaser B;Kaestner KH
衰老是由表观遗传状态的变化所驱动的，而我们对这些变化的理解只有一部分。我们对青春期和老年小鼠的胰腺β细胞进行了全面的表观基因组分析，该细胞是葡萄糖稳态的关键角色。我们观察到，在老年β细胞中，全球甲基化漂移导致整体甲基化水平更高。重要的是，我们发现了β细胞增殖和功能基因甲基化状态的靶向变化，这些基因反对全球甲基化漂移，是β细胞特异性的，并且与增殖程序的抑制和代谢调节因子的激活相关。这些靶向改变与年轻β细胞中的特定染色质标记和转录因子占用有关。引人注目的是，我们发现衰老小鼠的β细胞功能得到改善，正如甲基组和转录组的变化所预测的那样。因此，哺乳动物终末分化细胞的衰老并不总是与功能衰退相结合。
Aging is driven by changes of the epigenetic state that are only partially understood. We performed a comprehensive epigenomic analysis of the pancreatic β cell, key player in glucose homeostasis, in adolescent and very old mice. We observe a global methylation drift resulting in an overall more leveled methylome in old β cells. Importantly, we discover targeted changes in the methylation status of β cell proliferation and function genes that go against the global methylation drift, are specific to β cells, and correlate with repression of the proliferation program and activation of metabolic regulators. These targeted alterations are associated with specific chromatin marks and transcription factor occupancy in young β cells. Strikingly, we find β cell function improved in aged mice, as predicted by the changes in methylome and transcriptome. Thus, aging of terminally differentiated cells in mammals is not always coupled to functional decline.