Telomeric epigenetic response mediated by Gadd45a regulates stem cell aging and lifespan

• Published in: EMBO reports Vol. 19; no. 10
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.10.2018; Nature Publishing Group; John Wiley and Sons Inc
• Subjects: Ablation; Aging; Aging - genetics; Aging - metabolism; Animals; Base excision repair; Cell Cycle Proteins - genetics; Chromatin; Chromosomes; Clonal deletion; CpG islands; CpG Islands - genetics; Demethylation; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - genetics; Epigenesis, Genetic - genetics; Epigenetics; Fibroblasts; Gadd45a; Gadd45A protein; Heterochromatin; Intestinal Mucosa - metabolism; Intestine; Life span; Maintenance; Mice; Mice, Knockout; Nuclear Proteins - genetics; Repair; RNA - genetics; Rodents; Senescence; stem cell aging; Stem cell transplantation; Stem cells; Stem Cells - metabolism; Telomerase; Telomerase - genetics; telomere; Telomere - genetics; Telomeres; stem cell aging; Gadd45a; epigenetics; telomere
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.201745494

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. Synopsis Progressive shortening of telomeres triggers DDR and limits the regenerative capacity of adult stem cells. Ablation of Gadd45a restores heterochromatic structures at telomeres, rescues stem cell maintenance, and extends the lifespan of telomerase‐deficient mice. Gadd45a promotes DNA demethylation in telomerase deficient mice, inducing decondensed telomeric chromatin. Restoring telomeric heterochromatin attenuates DDR and improves the maintenance and function of intestinal stem cells. Interfering with Gadd45a or APE1 delays the replicative senescence of human primary fibroblasts. Progressive shortening of telomeres triggers DDR and limits the regenerative capacity of adult stem cells. Ablation of Gadd45a restores heterochromatic structures at telomeres, rescues stem cell maintenance, and extends the lifespan of telomerase‐deficient mice.