PASK links cellular energy metabolism with a mitotic self-renewal network to establish differentiation competence
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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-04-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/81717 |
| _version_ | 1797832837372575744 |
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| author | Michael Xiao Chia-Hua Wu Graham Meek Brian Kelly Dara Buendia Castillo Lyndsay EA Young Sara Martire Sajina Dhungel Elizabeth McCauley Purbita Saha Altair L Dube Matthew S Gentry Laura A Banaszynski Ramon C Sun Chintan K Kikani |
| author_facet | Michael Xiao Chia-Hua Wu Graham Meek Brian Kelly Dara Buendia Castillo Lyndsay EA Young Sara Martire Sajina Dhungel Elizabeth McCauley Purbita Saha Altair L Dube Matthew S Gentry Laura A Banaszynski Ramon C Sun Chintan K Kikani |
| author_sort | Michael Xiao |
| collection | DOAJ |
| description | 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 mitochondrial 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. |
| first_indexed | 2024-04-09T14:14:07Z |
| format | Article |
| id | doaj.art-697189baa2334a1aa47ad10289eafb8e |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-09T14:14:07Z |
| publishDate | 2023-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-697189baa2334a1aa47ad10289eafb8e2023-05-05T14:52:18ZengeLife Sciences Publications LtdeLife2050-084X2023-04-011210.7554/eLife.81717PASK links cellular energy metabolism with a mitotic self-renewal network to establish differentiation competenceMichael Xiao0Chia-Hua Wu1https://orcid.org/0000-0002-5361-5469Graham Meek2Brian Kelly3Dara Buendia Castillo4https://orcid.org/0000-0001-8955-2984Lyndsay EA Young5Sara Martire6Sajina Dhungel7Elizabeth McCauley8Purbita Saha9Altair L Dube10Matthew S Gentry11https://orcid.org/0000-0001-5253-9049Laura A Banaszynski12Ramon C Sun13https://orcid.org/0000-0002-3009-1850Chintan K Kikani14https://orcid.org/0000-0003-1140-0192Department of Biology, College of Arts and Sciences, University of Kentucky, Thomas Hunt Morgan Building, Lexington, United States; Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, United StatesDepartment of Biology, College of Arts and Sciences, University of Kentucky, Thomas Hunt Morgan Building, Lexington, United StatesDepartment of Biology, College of Arts and Sciences, University of Kentucky, Thomas Hunt Morgan Building, Lexington, United StatesDepartment of Biology, College of Arts and Sciences, University of Kentucky, Thomas Hunt Morgan Building, Lexington, United StatesDepartment of Biology, College of Arts and Sciences, University of Kentucky, Thomas Hunt Morgan Building, Lexington, United StatesMolecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, United StatesCecil H. and Ida Green Center for Reproductive Biology Sciences, Children’s Medical Center Research Institute, Department of Obstetrics & Gynecology, Hamon Center for Regenerative Science and Medicine at the University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Biology, College of Arts and Sciences, University of Kentucky, Thomas Hunt Morgan Building, Lexington, United StatesDepartment of Biology, College of Arts and Sciences, University of Kentucky, Thomas Hunt Morgan Building, Lexington, United StatesCecil H. and Ida Green Center for Reproductive Biology Sciences, Children’s Medical Center Research Institute, Department of Obstetrics & Gynecology, Hamon Center for Regenerative Science and Medicine at the University of Texas Southwestern Medical Center, Dallas, United StatesCecil H. and Ida Green Center for Reproductive Biology Sciences, Children’s Medical Center Research Institute, Department of Obstetrics & Gynecology, Hamon Center for Regenerative Science and Medicine at the University of Texas Southwestern Medical Center, Dallas, United StatesMolecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, United StatesCecil H. and Ida Green Center for Reproductive Biology Sciences, Children’s Medical Center Research Institute, Department of Obstetrics & Gynecology, Hamon Center for Regenerative Science and Medicine at the University of Texas Southwestern Medical Center, Dallas, United StatesMolecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, United States; Department of Neuroscience, College of Medicine, University of Kentucky, Lexington, United StatesDepartment of Biology, College of Arts and Sciences, University of Kentucky, Thomas Hunt Morgan Building, Lexington, United StatesQuiescent 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 mitochondrial 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.https://elifesciences.org/articles/81717Pax7self-renewalPASKglutaminemyogenesisWdr5 |
| spellingShingle | Michael Xiao Chia-Hua Wu Graham Meek Brian Kelly Dara Buendia Castillo Lyndsay EA Young Sara Martire Sajina Dhungel Elizabeth McCauley Purbita Saha Altair L Dube Matthew S Gentry Laura A Banaszynski Ramon C Sun Chintan K Kikani PASK links cellular energy metabolism with a mitotic self-renewal network to establish differentiation competence eLife Pax7 self-renewal PASK glutamine myogenesis Wdr5 |
| title | PASK links cellular energy metabolism with a mitotic self-renewal network to establish differentiation competence |
| title_full | PASK links cellular energy metabolism with a mitotic self-renewal network to establish differentiation competence |
| title_fullStr | PASK links cellular energy metabolism with a mitotic self-renewal network to establish differentiation competence |
| title_full_unstemmed | PASK links cellular energy metabolism with a mitotic self-renewal network to establish differentiation competence |
| title_short | PASK links cellular energy metabolism with a mitotic self-renewal network to establish differentiation competence |
| title_sort | pask links cellular energy metabolism with a mitotic self renewal network to establish differentiation competence |
| topic | Pax7 self-renewal PASK glutamine myogenesis Wdr5 |
| url | https://elifesciences.org/articles/81717 |
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