Stabilization of heterochromatin by CLOCK promotes stem cell rejuvenation and cartilage regeneration
Authors: Jing Qu
Qiaoran Wang
Zeming Wu
Pedro Guillen
Tomoaki Hishida
Weiqi Zhang
Qi Zhou
Chuqian Liang
Zehua Wang
Si Wang
Kaowen Yan
Juan Carlos Izpisua Belmonte
Moshi Song
Piu Chan
Guang-Hui Liu
Wei Li
Yanning Cai
Zunpeng Liu
Liang Sun
Journal: Cell Research (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: circadian clock; aging; stem cells; CLOCK; hMSC
Affiliations: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China., University of Chinese Academy of Sciences, Beijing, 100049, China., State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China., Institute for Stem Cell and Regeneration, CAS, Beijing, 100101, China., Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China., CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China., The MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, 100730, China., Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA., Clinica Cemtro, Av. del Ventisquero de la Condesa, 42, Madrid, 28035, Spain., University of Chinese Academy of Sciences, Beijing, 100049, China. ., Institute for Stem Cell and Regeneration, CAS, Beijing, 100101, China. ., CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China. ., China National Center for Bioinformation, Beijing, 100101, China. ., State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. ., State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. ., Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China. .

Abstract:  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. 

Retracted: No

PubPeer comments:
 Astonishing data in this  paper . For example, compare the data points on Figure 1b, MP samples with 1L, clock- - samples. Also compare the points on each of 1J. Superimposable. https: www.nature.com articles s41422-020-0385-7 figures 1 I shall continue. Compare 2E  alpha Sat with anti clock antibody to the same from  Line-1 . Superimposable. Compare 2i LBR and HP1 gamma panels red bars have the same data points. Superimposable. https: www.nature.com articles s41422-020-0385-7 figures 2 I shall continue. Fig 4B the graphs have the same data. Superimposable. Fig 4D is littered with the same data. Superimposable. Fig 4E  rDNA green and red. Superimposable. https: www.nature.com articles s41422-020-0385-7 figures 4 I shall continue. Fig 5B Compare the data points for the red and the lighter green. Superimposable. Fig 5F compare the red bar to the blue bar data. Superimposable. Fig 5G compare the blue bar to the green bar. Superimposable. https: www.nature.com articles s41422-020-0385-7 figures 5 I shall go on. Fig 6G compare the Luc daa in red. Superimposable. https: www.nature.com articles s41422-020-0385-7 figures 6 I am SURE that this is an  honest mistake that occured during manuscript preparation, but has no effect on the conclusions . This took minutes to spot. Great job on the  peer review . These authors work should be interrogated to find more of this garbage. They publish a lot of high profile  papers . Yes I like finger quotes. ,