Telomeric epigenetic response mediated by Gadd45a regulates stem cell aging and lifespan
Telomeric epigenetic response mediated by Gadd45a regulates stem cell aging and lifespan
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Gadd45a介导的端粒表观遗传反应调节干细胞衰老和寿命
DOI：
10.15252/embr.201745494
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发表时间：
2018-10-01
期刊：
影响因子：
7.7
通讯作者：
Ju, Zhenyu
中科院分区：
文献类型：
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作者：
Diao, Daojun;Wang, Hu;Ju, Zhenyu
在哺乳动物衰老过程中，端粒的逐渐磨损触发DNA损伤反应（DDR）并限制成体干细胞的再生能力。有趣的是，端粒完整性不仅由端粒长度决定，还由端粒/亚端粒区域的表观遗传状态决定。然而，由端粒缩短诱导的DDR与衰老中的表观遗传修饰之间的功能相互作用仍不清楚。在这里，我们发现Gadd 45 a的缺失改善了肠干细胞（ISCs）的维持和功能，并延长了端粒酶缺陷小鼠（G3 Terc −/−）的寿命。从机制上讲，Gadd 45 a通过诱导特异性位于短端粒亚端粒区域的CpG岛的碱基切除修复依赖性去甲基化，促进DDR信号传导的容许染色质状态的产生。Gadd 45 a的缺失促进了亚端粒区域的染色质致密化，并减弱了G3 Terc −/− ISC短端粒处的DDR起始。用碱基切除修复的小分子抑制剂治疗减少DDR并改善G3 Terc −/− ISC的维持和功能。综上所述，我们的研究提出了一种通过靶向表观遗传修饰剂来增强干细胞功能和延长寿命的治疗方法。
Progressive attrition of telomeres triggers DNA damage response (DDR) and limits the regenerative capacity of adult stem cells during mammalian aging. Intriguingly, telomere integrity is not only determined by telomere length but also by the epigenetic status of telomeric/sub‐telomeric regions. However, the functional interplay between DDR induced by telomere shortening and epigenetic modifications in aging remains unclear. Here, we show that deletion of Gadd45a improves the maintenance and function of intestinal stem cells (ISCs) and prolongs lifespan of telomerase‐deficient mice (G3Terc−/−). Mechanistically, Gadd45a facilitates the generation of a permissive chromatin state for DDR signaling by inducing base excision repair‐dependent demethylation of CpG islands specifically at sub‐telomeric regions of short telomeres. Deletion of Gadd45a promotes chromatin compaction in sub‐telomeric regions and attenuates DDR initiation at short telomeres of G3Terc−/− ISCs. Treatment with a small molecule inhibitor of base excision repair reduces DDR and improves the maintenance and function of G3Terc−/− ISCs. Taken together, our study proposes a therapeutic approach to enhance stem cell function and prolong lifespan by targeting epigenetic modifiers.