Rev-Erb co-regulates muscle regeneration via tethered interaction with the NF-Y cistrome
Objective: The loss of skeletal muscle mass and strength are a central feature of traumatic injury and degenerative myopathies. Unfortunately, pharmacological interventions typically fail to stem the long-term decline in quality of life. Reduced Rev-Erb-mediated gene suppression in cultured C2C12 my...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2017-07-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877817302788 |
| _version_ | 1819261959675052032 |
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| author | Ryan D. Welch Chun Guo Monideepa Sengupta Katherine J. Carpenter Natalie A. Stephens Stacy A. Arnett Marvin J. Meyers Lauren M. Sparks Steven R. Smith Jinsong Zhang Thomas P. Burris Colin A. Flaveny |
| author_facet | Ryan D. Welch Chun Guo Monideepa Sengupta Katherine J. Carpenter Natalie A. Stephens Stacy A. Arnett Marvin J. Meyers Lauren M. Sparks Steven R. Smith Jinsong Zhang Thomas P. Burris Colin A. Flaveny |
| author_sort | Ryan D. Welch |
| collection | DOAJ |
| description | Objective: The loss of skeletal muscle mass and strength are a central feature of traumatic injury and degenerative myopathies. Unfortunately, pharmacological interventions typically fail to stem the long-term decline in quality of life. Reduced Rev-Erb-mediated gene suppression in cultured C2C12 myoblasts has been shown to stimulate myoblast differentiation. Yet the mechanisms that allow Rev-Erb to pleiotropically inhibit muscle differentiation are not well understood. In this study, we sought to elucidate the role of Rev-Erb in the regulation of muscle differentiation and regeneration in vivo.
Methods: Using Rev-Erbα/β shRNAs, pharmacological ligands, and Rev-Erbα null and heterozygous mice, we probed the mechanism of Rev-Erbα/β regulation of muscle differentiation and muscle regeneration.
Results: ChIP seq analysis of Rev-Erb in differentiating myoblasts showed that Rev-Erbα did not transcriptionally regulate muscle differentiation through cognate Rev-Erb/ROR-response elements but through possible interaction with the cell fate regulator NF-Y at CCAAT-motifs. Muscle differentiation is stimulated by Rev-Erb release from CCAAT-motifs at promoter and enhancer elements of a number of myogenesis proteins. Partial loss of Rev-Erb expression in mice heterozygous for Rev-Erbα accelerated muscle repair in vivo whereas Rev-Erb knockout mice showed deficiencies in regenerative repair compared to wild type mice. These phenotypic differences between heterozygous and knockout mice were not apparently dependent on MRF induction in response to injury. Similarly, pharmacological disruption of Rev-Erb suppressive activity in injured muscle accelerated regenerative repair in response to acute injury.
Conclusions: Disrupting Rev-Erb activity in injured muscle accelerates regenerative muscle repair/differentiation through transcriptional de-repression of myogenic programs. Rev-Erb, therefore, may be a potent therapeutic target for a myriad of muscular disorders. |
| first_indexed | 2024-12-23T19:50:05Z |
| format | Article |
| id | doaj.art-208d3ae9d5de4203b825c6f7062c5709 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-23T19:50:05Z |
| publishDate | 2017-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-208d3ae9d5de4203b825c6f7062c57092022-12-21T17:33:24ZengElsevierMolecular Metabolism2212-87782017-07-016770371410.1016/j.molmet.2017.05.001Rev-Erb co-regulates muscle regeneration via tethered interaction with the NF-Y cistromeRyan D. Welch0Chun Guo1Monideepa Sengupta2Katherine J. Carpenter3Natalie A. Stephens4Stacy A. Arnett5Marvin J. Meyers6Lauren M. Sparks7Steven R. Smith8Jinsong Zhang9Thomas P. Burris10Colin A. Flaveny11Department of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USADepartment of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USADepartment of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USADepartment of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USATranslational Research Institutes of Metabolism and Diabetes, Florida Hospital and Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32804, USACenter for World Health and Medicine at Saint Louis University, Saint Louis, MO 63104, USACenter for World Health and Medicine at Saint Louis University, Saint Louis, MO 63104, USATranslational Research Institutes of Metabolism and Diabetes, Florida Hospital and Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32804, USATranslational Research Institutes of Metabolism and Diabetes, Florida Hospital and Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32804, USADepartment of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USADepartment of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USADepartment of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USAObjective: The loss of skeletal muscle mass and strength are a central feature of traumatic injury and degenerative myopathies. Unfortunately, pharmacological interventions typically fail to stem the long-term decline in quality of life. Reduced Rev-Erb-mediated gene suppression in cultured C2C12 myoblasts has been shown to stimulate myoblast differentiation. Yet the mechanisms that allow Rev-Erb to pleiotropically inhibit muscle differentiation are not well understood. In this study, we sought to elucidate the role of Rev-Erb in the regulation of muscle differentiation and regeneration in vivo. Methods: Using Rev-Erbα/β shRNAs, pharmacological ligands, and Rev-Erbα null and heterozygous mice, we probed the mechanism of Rev-Erbα/β regulation of muscle differentiation and muscle regeneration. Results: ChIP seq analysis of Rev-Erb in differentiating myoblasts showed that Rev-Erbα did not transcriptionally regulate muscle differentiation through cognate Rev-Erb/ROR-response elements but through possible interaction with the cell fate regulator NF-Y at CCAAT-motifs. Muscle differentiation is stimulated by Rev-Erb release from CCAAT-motifs at promoter and enhancer elements of a number of myogenesis proteins. Partial loss of Rev-Erb expression in mice heterozygous for Rev-Erbα accelerated muscle repair in vivo whereas Rev-Erb knockout mice showed deficiencies in regenerative repair compared to wild type mice. These phenotypic differences between heterozygous and knockout mice were not apparently dependent on MRF induction in response to injury. Similarly, pharmacological disruption of Rev-Erb suppressive activity in injured muscle accelerated regenerative repair in response to acute injury. Conclusions: Disrupting Rev-Erb activity in injured muscle accelerates regenerative muscle repair/differentiation through transcriptional de-repression of myogenic programs. Rev-Erb, therefore, may be a potent therapeutic target for a myriad of muscular disorders.http://www.sciencedirect.com/science/article/pii/S2212877817302788Rev-ErbNuclear factor-YACCAAT-Binding motifMyogenesisMuscle regenerationSR8278 |
| spellingShingle | Ryan D. Welch Chun Guo Monideepa Sengupta Katherine J. Carpenter Natalie A. Stephens Stacy A. Arnett Marvin J. Meyers Lauren M. Sparks Steven R. Smith Jinsong Zhang Thomas P. Burris Colin A. Flaveny Rev-Erb co-regulates muscle regeneration via tethered interaction with the NF-Y cistrome Molecular Metabolism Rev-Erb Nuclear factor-YA CCAAT-Binding motif Myogenesis Muscle regeneration SR8278 |
| title | Rev-Erb co-regulates muscle regeneration via tethered interaction with the NF-Y cistrome |
| title_full | Rev-Erb co-regulates muscle regeneration via tethered interaction with the NF-Y cistrome |
| title_fullStr | Rev-Erb co-regulates muscle regeneration via tethered interaction with the NF-Y cistrome |
| title_full_unstemmed | Rev-Erb co-regulates muscle regeneration via tethered interaction with the NF-Y cistrome |
| title_short | Rev-Erb co-regulates muscle regeneration via tethered interaction with the NF-Y cistrome |
| title_sort | rev erb co regulates muscle regeneration via tethered interaction with the nf y cistrome |
| topic | Rev-Erb Nuclear factor-YA CCAAT-Binding motif Myogenesis Muscle regeneration SR8278 |
| url | http://www.sciencedirect.com/science/article/pii/S2212877817302788 |
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