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

doi:10.1016/j.celrep.2023.112590

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

Cell Rep. 2023 Jun 27;42(6):112590. doi: 10.1016/j.celrep.2023.112590. Epub 2023 May 31.

Authors

Affiliations

¹ 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. Electronic address: shogo.sato@bio.tamu.edu.
² 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.
³ Center for Epigenetics and Metabolism, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA.
⁴ Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA; Altos Labs, San Diego, CA, USA.
⁵ Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA.
⁶ Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA.
⁷ UC Irvine Diabetes Center, Sue and Bill Gross Stem Cell Research Center, Department of Medicine, University of California, Irvine, Irvine, CA, USA.
⁸ Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA; Altos Labs, San Diego, CA, USA. Electronic address: jcbelmonte@altoslabs.com.

PMID: 37261952
DOI: 10.1016/j.celrep.2023.112590

Abstract

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.

Keywords: CP: Stem cell research; Cryptochrome 1; circadian clock; iPSC reprogramming; metabolism; pluripotent stem cells; stem cell research; sterol regulatory element binding protein 1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
Cellular Reprogramming
Circadian Clocks* / genetics
Cryptochromes* / metabolism
Mice
Pluripotent Stem Cells*
Signal Transduction

Substances

Cry1 protein, mouse
Cryptochromes