Metabolic regulation of muscle stem cell histone acetylation landscape during regeneration
Abstract/Contents
- Abstract
- Muscle is a highly glycolytic tissue, yet the impact of glucose metabolism on muscle stem cell function remains unresolved. Here we identify glucose metabolism as an essential driver of histone acetylation during muscle stem cell (MuSC) fate transitions in myogenesis. We use mass cytometry (CyTOF) and flow cytometry to characterize histone acetylation state at the single cell level following injury. We demonstrate an increase in histone acetylation upon MuSC activation, followed by a global reduction that is required for commitment to differentiation. This epigenetic switch is driven by reduced metabolic flux through pyruvate dehydrogenase (PDH), which generates acetyl-CoA, the substrate for histone acetylation. Activation of PDH in myoblast progenitors increases histone acetylation and impedes myogenic differentiation. In vivo, knockout of PDH inhibitory kinases, PDK2 and PDK4, leads to increased histone acetylation and accumulation of undifferentiated MuSCs following injury, resulting in impaired muscle regeneration. Conversely, high fat diet induces skeletal muscle Pdk2 and Pdk4 overexpression leading to aberrant PDH phosphorylation, dysregulated histone acetylation in MuSCs, and reduced MuSC expansion after injury. These studies identify PDH as a previously unrecognized metabolic mediator of histone acetylation landscape crucial to myogenic differentiation and muscle regeneration.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2017 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Yucel, Nora Deniz |
|---|---|
| Associated with | Stanford University, Department of Genetics. |
| Primary advisor | Blau, Helen M |
| Thesis advisor | Blau, Helen M |
| Thesis advisor | Fuller, Margaret |
| Thesis advisor | Montgomery, Stephen, 1979- |
| Thesis advisor | Sage, Julien |
| Advisor | Fuller, Margaret |
| Advisor | Montgomery, Stephen, 1979- |
| Advisor | Sage, Julien |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Nora Deniz Yucel. |
|---|---|
| Note | Submitted to the Department of Genetics. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2017. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2017 by Nora Deniz Yucel
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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