Clock, short for Circadian Locomotor Output Cycles Kaput, is a core circadian clock gene. It is fundamental in regulating the circadian rhythm and mediates multiple biological processes. The circadian mechanism involving Clock and other core circadian genes like BMAL1, PER, and CRY is crucial for the regulation of cellular metabolism, and disruptions may lead to metabolic health issues such as obesity, metabolic syndrome, and type 2 diabetes [1].

In glioblastoma (GBM) mouse and patient-derived xenograft models, CLOCK-directed olfactomedin like 3 (OLFML3) expression causes hypoxia-inducible factor 1-alpha (HIF1α)-mediated transcriptional upregulation of periostin (POSTN), which promotes tumor angiogenesis via activation of the TANK-binding kinase 1 (TBK1) signaling in endothelial cells. Blockade of the CLOCK-directed POSTN-TBK1 axis inhibits tumor progression and angiogenesis, suggesting CLOCK as an actionable therapeutic target for GBM [2].

In human mesenchymal stem cell (hMSC) models, CLOCK expression decreased during aging. CLOCK deficiency accelerated hMSC senescence, while overexpression, even of a transcriptionally inactive form, rejuvenated aged hMSCs. Mechanistically, CLOCK formed complexes with nuclear lamina proteins and KAP1 to maintain heterochromatin architecture. Gene therapy with lentiviral vectors encoding CLOCK promoted cartilage regeneration and attenuated age-related articular degeneration in mice, demonstrating a non-canonical role of CLOCK in stabilizing heterochromatin, promoting tissue regeneration, and mitigating aging-associated chronic diseases [3].

In conclusion, Clock is essential for regulating the circadian rhythm and various biological processes. Model-based research, especially using mouse models in glioblastoma and hMSC studies, has revealed its role in tumor angiogenesis and stem cell-related processes, offering potential therapeutic targets for diseases like GBM and age-related articular degeneration.