The circadian clock CRY1 regulates pluripotent stem cell identity and somatic cell reprogramming
Shogo Sato,
Tomoaki Hishida,
Kenichiro Kinouchi,
Fumiaki Hatanaka,
Yumei Li,
Quy Nguyen,
Yumay Chen,
Ping H. Wang,
Kai Kessenbrock,
Wei Li,
Juan Carlos Izpisua Belmonte,
Paolo Sassone-Corsi
Affiliations
Shogo Sato
Center for Epigenetics and Metabolism, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA; Center for Biological Clocks Research, Department of Biology, Texas A&M University, College Station, TX, USA; Corresponding author
Tomoaki Hishida
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA; Laboratory of Biological Chemistry, School of Pharmaceutical Sciences, Wakayama Medical University, Wakayama, Japan
Kenichiro Kinouchi
Center for Epigenetics and Metabolism, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA
Fumiaki Hatanaka
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA; Altos Labs, San Diego, CA, USA
Yumei Li
Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA
Quy Nguyen
Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA
Yumay Chen
UC Irvine Diabetes Center, Sue and Bill Gross Stem Cell Research Center, Department of Medicine, University of California, Irvine, Irvine, CA, USA
Ping H. Wang
UC Irvine Diabetes Center, Sue and Bill Gross Stem Cell Research Center, Department of Medicine, University of California, Irvine, Irvine, CA, USA
Kai Kessenbrock
Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA
Wei Li
Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA
Juan Carlos Izpisua Belmonte
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA; Altos Labs, San Diego, CA, USA; Corresponding author
Paolo Sassone-Corsi
Center for Epigenetics and Metabolism, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA
Summary: 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) reprogramming, resulting in impaired iPSC reprogramming efficiency. Collectively, these results suggest the functional implication of CRY1 in pluripotent reprogramming and ontogenesis, thereby dictating PSC identity.
