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

Autor: Jing Qu, Pedro Guillen, Kaowen Yan, Piu Chan, Liang Sun, Si Wang, Yanning Cai, Tomoaki Hishida, Zeming Wu, Weiqi Zhang, Qiaoran Wang, Juan Carlos Izpisua Belmonte, Chuqian Liang, Zehua Wang, Wei Li, Qi Zhou, Moshi Song, Guang-Hui Liu, Zunpeng Liu
Rok vydání: 2020
Předmět:
Zdroj: Cell Research
ISSN: 1748-7838
1001-0602
DOI: 10.1038/s41422-020-0385-7
Popis: 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.
Databáze: OpenAIRE
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