GSE145019 Stabilization of Heterochromatin by CLOCK Counteracts hMSC Senescence and Articular Degeneration

Contributor : Guanghui LiuSeries Type : Expression profiling by high throughput sequencing ; Genome binding/occupancy profiling by high throughput sequencing ; OtherOrganism : Homo sapiens ; Mus musculusAccumulating evidence indicates the close association between the circadian clock and the aging process. However, it is unclear whether and how the circadian clock proteins regulate stem cell aging. Here, we identified a noncanonical transcriptional activator-independent role of CLOCK, a core component of the molecular circadian clock machinery, in counteracting human mesenchymal stem cell (hMSC) senescence. CLOCK expression was decreased during hMSC aging. In addition, CLOCK deficiency accelerated hMSC senescence, whereas CLOCK overexpression attenuated physiological and pathological hMSC senescence. Mechanistic studies revealed that CLOCK formed complexes with nuclear lamina proteins and KAP1, thus maintaining heterochromatin architecture and stabilizing genomic repetitive sequences. Finally, gene therapy with lentiviral vectors encoding CLOCK promoted cartilage regeneration and attenuated age-related osteoarthritis in mice. These findings reveal a novel role of CLOCK independent of its transcriptional activation activity in the stabilization of heterochromatin and alleviation of hMSC senescence, providing a potential therapeutic target for treating aging-associated articular degeneration.

Source: GEO: Gene Expression Omnibus - February 11, 2020 Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Genome binding/occupancy profiling by high throughput sequencing Other Homo sapiens Mus musculus Source Type: research