Volume 31, No 2, Feb 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 2, February 2021: 187-205   |  Open Access

ORIGINAL ARTICLES

Stabilization of heterochromatin by CLOCK promotes stem cell rejuvenation and cartilage regeneration

Chuqian Liang^1,2 , Zunpeng Liu^2,3 , Moshi Song^1,2,4 , Wei Li⁵ , Zeming Wu^2,3 , Zehua Wang^2,3 , Qiaoran Wang^2,6 , Si Wang^1,2,4,5 , Kaowen Yan^1,2,4 , Liang Sun⁷ , Tomoaki Hishida⁸ , Yanning Cai⁵ , Juan Carlos Izpisua Belmonte⁸ , Pedro Guillen⁹ , Piu Chan⁵ , Qi Zhou^2,3,4 , Weiqi Zhang^2,4,6,10,* , Jing Qu^2,3,4,* , Guang-Hui Liu^1,2,4,5,*

¹State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
²University of Chinese Academy of Sciences, Beijing 100049, China
³State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
⁴Institute for Stem Cell and Regeneration, CAS, Beijing 100101, China
⁵Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
⁶CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
⁷The MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing 100730, China
⁸Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
⁹Clinica Cemtro, Av. del Ventisquero de la Condesa, 42, Madrid 28035, Spain
¹⁰China National Center for Bioinformation, Beijing 100101, China
These authors contributed equally: Chuqian Liang, Zunpeng Liu, Moshi Song Correspondence: Weiqi Zhang(zhangwq@big.ac.cn)Jing Qu(qujing@ioz.ac.cn)Guang-Hui Liu(ghliu@ioz.ac.cn)

Accumulating evidence indicates an association between the circadian clock and the aging process. However, it remains elusive whether the deregulation of circadian clock proteins underlies stem cell aging and whether they are targetable for the alleviation of aging-associated syndromes. Here, we identified a transcription factor-independent role of CLOCK, a core component of the molecular circadian clock machinery, in counteracting human mesenchymal stem cell (hMSC) decay. CLOCK expression was decreased during hMSC aging. In addition, CLOCK deficiency accelerated hMSC senescence, whereas the overexpression of CLOCK, even as a transcriptionally inactive form, rejuvenated physiologically and pathologically aged hMSCs. Mechanistic studies revealed that CLOCK formed complexes with nuclear lamina proteins and KAP1, thus maintaining heterochromatin architecture and stabilizing repetitive genomic sequences. Finally, gene therapy with lentiviral vectors encoding CLOCK promoted cartilage regeneration and attenuated age-related articular degeneration in mice. These findings demonstrate a noncanonical role of CLOCK in stabilizing heterochromatin, promoting tissue regeneration, and mitigating aging-associated chronic diseases.

https://doi.org/10.1038/s41422-020-0385-7

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