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

作　　者：Chuqian Liang Zunpeng Liu Moshi Song Wei Li Zeming Wu Zehua Wang Qiaoran Wang Si Wang Kaowen Yan Liang Sun Tomoaki Hishida Yanning Cai Juan Carlos lzpisua Belmonte Pedro Guillen Piu Chan Qi Zhou Weiqi Zhang Jing Qu Guang-Hui Liu 

机构地区：[1]State Key Laboratory of Membrane Biology,Institute of Zoology,Chinese Academy of Sciences,Beijing 100101,China [2]University of Chinese Academy of Sciences,Beijing 100049,China [3]State Key Laboratory of Stem Cell and Reproductive Biology,Institute of Zoology,Chinese Academy of Sciences,Beijing 100101,China [4]lnstitute for Stem Cell and Regeneration,CAS,Beijing 100101,China [5]Advanced Innovation Center for Human Brain Protection,National Clinical Research Center for Geriatric Disorders,Xuanwu Hospital Capital Medical University,Beijing 100053,China [6]CAS Key Laboratory of Genomic and Precision Medicine,Beijing Institute of Genomics,Chinese Academy of Sciences,Beijing 100101,China [7]The MOH Key Laboratory of Geriatrics,Beijing Hospital,National Center of Gerontology,Beijing 100730,China [8]Gene Expression Laboratory,Salk Institute for Biological Studies,La Jolla,CA 92037,USA [9]Clinica Cemtro,Av.del Ventisquero de la Condesa,42,Madrid 28035,Spain [10]China National Center for Bioinformation,Beijing 100101,China

出　　处：《Cell Research》2021年第2期187-205,共19页细胞研究（英文版）

基　　金：This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16010100);the National Key R&D Program of China(2018YFC2000100,2018YFA0107203,2017VFA0102802,2017YFA0103304,2015CB964800,2019YFA0110100);the National Natural Science Foundation of China(81861168034,81921006,81625009,91749202,31671429,91949209,81671377,91749123,81822018,81870228,31801010,81922027,81701388);Program of Beijing Municipal Science and Technology Commission(Z191100001519005);Beijing Natural Science Foundation(Z190019);Beijing Municipal Commission of Health and Family Planning(PXM2018_026283_000002);Advanced Innovation Center for Human Brain Protection(3500-1192012);the Key Research Program of the Chinese Academy of Sciences(KFZD-SW-221);K.C.Wong Education Foundation(GJTD-2019-06,GJTD-2019-08);Youth Innovation Promotion Association of CAS(2016093);the State Key Laboratory of Stem Cell and Reproductive Biology;the State Key Laboratory of Membrane Biology;P.G.was supported by MAPHRE and Fundacion Pedro Guillen.

摘　　要：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.

关 键 词：DEGENERATION stabilizing CLOCK 

分 类 号：R32[医药卫生—人体解剖和组织胚胎学]