The circadian clock CRY1 regulates pluripotent stem cell identity and somatic cell reprogramming

Distinct metabolic conditions rewire circadian-clock-controlled signaling pathways leading to the de novo construction of signal transduction networks. However, it remains unclear whether metabolic hallmarks unique to pluripotent stem cells (PSCs) are connected to clock functions. Reprogramming somatic cells to a pluripotent state, here we highlighted non-canonical functions of the circadian repressor CRY1 specific to PSCs. Metabolic reprogramming, including AMPK inactivation and SREBP1 activation, was coupled with the accumulation of CRY1 in PSCs. Functional assays verified that CRY1 is required for the maintenance of self-renewal capacity, colony organization, and metabolic signatures. Genome-wide occupancy of CRY1 identified CRY1-regulatory genes enriched in development and differentiation in PSCs, albeit not somatic cells. Last, cells lacking CRY1 exhibit differential gene expression profiles during induced PSC (iPSC) reprog-ramming, resulting in impaired iPSC reprogramming efficiency. Collectively, these results suggest the func-tional implication of CRY1 in pluripotent reprogramming and ontogenesis, thereby dictating PSC identity.

Automated summary

Distinct metabolic conditions in pluripotent stem cells (PSCs) are connected to clock functions through the circadian repressor CRY1. Metabolic reprogramming and the accumulation of CRY1 are essential for self-renewal capacity, colony organization, and metabolic signatures in PSCs. CRY1 regulates developmental and differentiation genes in PSCs, and its absence impairs induced PSC (iPSC) reprogramming efficiency.