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Telomeric epigenetic response mediated by Gadd45a regulates stem cell aging and lifespan
Author(s) -
Diao Daojun,
Wang Hu,
Li Tangliang,
Shi Zhencan,
Jin Xiaoqing,
Sperka Tobias,
Zhu Xudong,
Zhang Meimei,
Yang Fan,
Cong Yusheng,
Shen Li,
Zhan Qimin,
Yan Jing,
Song Zhangfa,
Ju Zhenyu
Publication year - 2018
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201745494
Subject(s) - epigenetics , stem cell , telomere , biology , cellular aging , microbiology and biotechnology , epigenesis , genetics , dna methylation , gene , gene expression
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 ( ISC s) and prolongs lifespan of telomerase‐deficient mice (G3 Terc −/− ). 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 G3 Terc −/− ISC s. Treatment with a small molecule inhibitor of base excision repair reduces DDR and improves the maintenance and function of G3 Terc −/− ISC s. Taken together, our study proposes a therapeutic approach to enhance stem cell function and prolong lifespan by targeting epigenetic modifiers.