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Article

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

View ORCID ProfileDaojun Diao, Hu Wang, View ORCID ProfileTangliang Li, Zhencan Shi, Xiaoqing Jin, Tobias Sperka, Xudong Zhu, Meimei Zhang, Fan Yang, Yusheng Cong, Li Shen, Qimin Zhan, Jing Yan, Zhangfa Song, View ORCID ProfileZhenyu Ju
DOI 10.15252/embr.201745494 | Published online 20.08.2018
EMBO reports (2018) e45494
Daojun Diao
Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China
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Hu Wang
Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China
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Tangliang Li
Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China
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Zhencan Shi
Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China
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Xiaoqing Jin
Zhejiang Hospital, Hangzhou, China
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Tobias Sperka
Leibniz Institute on Aging, Fritz Lipmann Institute (FLI), Jena, Germany
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Xudong Zhu
Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China
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Meimei Zhang
Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China
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Fan Yang
Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China
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Yusheng Cong
Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China
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Li Shen
Life Sciences Institute, Zhejiang University, Hangzhou, China
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Qimin Zhan
State Key Laboratory of Molecular Oncology and Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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Jing Yan
Zhejiang Hospital, Hangzhou, China
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Zhangfa Song
Department of Colorectal Surgery, Sir Run Run Shaw Hospital affiliated to Zhejiang University, Hangzhou, China
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Zhenyu Ju
Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, ChinaInstitute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China
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Author Affiliations

  1. Daojun Diao (diaodaojun{at}hotmail.com)*,1,†,
  2. Hu Wang2,†,
  3. Tangliang Li2,†,
  4. Zhencan Shi1,
  5. Xiaoqing Jin3,
  6. Tobias Sperka4,
  7. Xudong Zhu2,
  8. Meimei Zhang2,
  9. Fan Yang1,
  10. Yusheng Cong2,
  11. Li Shen5,
  12. Qimin Zhan6,
  13. Jing Yan3,
  14. Zhangfa Song7 and
  15. Zhenyu Ju (zhenyuju{at}163.com)*,1,2
  1. 1Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China
  2. 2Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China
  3. 3Zhejiang Hospital, Hangzhou, China
  4. 4Leibniz Institute on Aging, Fritz Lipmann Institute (FLI), Jena, Germany
  5. 5Life Sciences Institute, Zhejiang University, Hangzhou, China
  6. 6State Key Laboratory of Molecular Oncology and Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
  7. 7Department of Colorectal Surgery, Sir Run Run Shaw Hospital affiliated to Zhejiang University, Hangzhou, China
  1. ↵* Corresponding author. Tel: +86 020 85224362; E‐mail: diaodaojun{at}hotmail.com
    Corresponding author. Tel: +86 571 28861695; Fax: +86 571 28861695; E‐mail: zhenyuju{at}163.com
  1. ↵† These authors contributed equally to this work

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Abstract

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

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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.

  • epigenetics
  • Gadd45a
  • stem cell aging
  • telomere

EMBO Reports (2018) e45494

  • Received November 14, 2017.
  • Revision received July 26, 2018.
  • Accepted July 27, 2018.
  • © 2018 The Authors
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