Quiescent stem cells are activated in response to a mechanical or chemical injury to their tissue niche. Activated cells rapidly generate a heterogeneous progenitor population that regenerates the damaged tissues. While the transcriptional cadence that generates heterogeneity is known, the metabolic pathways influencing the transcriptional machinery to establish a heterogeneous progenitor population remains unclear. Here, we describe a novel pathway downstream of mitochondrial glutamine metabolism that confers stem cell heterogeneity and establishes differentiation competence by countering post-mitotic self-renewal machinery. We discovered that mito-chondrial glutamine metabolism induces CBP/EP300-dependent acetylation of stem cell-specific kinase, PAS domain-containing kinase (PASK), resulting in its release from cytoplasmic granules and subsequent nuclear migration. In the nucleus, PASK catalytically outcompetes mitotic WDR5-anaphase-promoting complex/cyclosome (APC/C) interaction resulting in the loss of post-mitotic Pax7 expression and exit from self-renewal. In concordance with these findings, genetic or pharmacological inhibition of PASK or glutamine metabolism upregulated Pax7 expression, reduced stem cell heterogeneity, and blocked myogenesis in vitro and muscle regeneration in mice. These results explain a mechanism whereby stem cells co-opt the proliferative functions of glutamine metabolism to generate transcriptional heterogeneity and establish differentiation competence by countering the mitotic self-renewal network via nuclear PASK.
|State||Published - Apr 2023|
Bibliographical noteFunding Information:
We acknowledge Jared Rutter and Wojciech Swiatek for providing a PASK inhibitor. In addition, we thank Cory Dungan (Center for Muscle Biology, University of Kentucky) and Kevin Murach (University of Arkansas Medical Center) for stimulating discussion and providing resources, reagents, and training in performing muscle histology. Funding This work was supported by funding from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), 1R01AR073906-01A1, and the College of Arts and Science start-up support to CKK. RCS is supported through NIH R01 grant AG066653-01; St. Baldrick’s career development award; Rally foundation independent investigator grant; V-scholar foundation award; and University of Kentucky College of Medicine and Markey Cancer Center start-up funds, and from the National Cancer Institute and NIH/NCI F99CA264165 (LEAY). LAB is supported by the National Institute of General Medical Sciences (NIGMS) GM124958, Welch Foundation I-2025, and American Cancer Society (134230-RSG-20-043-01-DMC) and to SM (fellowship support from UT Southwestern Medical Center Hamon Center for Regenerative Sciences and Medicine).
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ASJC Scopus subject areas
- Neuroscience (all)
- Biochemistry, Genetics and Molecular Biology (all)
- Immunology and Microbiology (all)