TY - JOUR
T1 - Dynamic enhancers control skeletal muscle identity and reprogramming
AU - Ramachandran, Krithika
AU - Senagolage, Madhavi D.
AU - Sommars, Meredith A.
AU - Futtner, Christopher R.
AU - Omura, Yasuhiro
AU - Allred, Amanda L.
AU - Barish, Grant D.
N1 - Funding Information:
Funding for this work was provided by National Institutes of Health https://www.nih.gov/ grants R01DK108987 (GDB) and R01HD089552 (GDB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Drs. Joseph Bass and Hee-kyung Hong and Northwestern University?s Comprehensive Metabolic Core for help with voluntary wheel running and associated analysis. We also thank Drs. Elizabeth McNally, Alexis Demonbreun, and Mattia Quattrocelli for fiber-typing protocols and helpful discussion of the manuscript.
Publisher Copyright:
© This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
PY - 2019
Y1 - 2019
N2 - Skeletal muscles consist of fibers of differing metabolic activities and contractility, which become remodeled in response to chronic exercise, but the epigenomic basis for muscle identity and adaptation remains poorly understood. Here, we used chromatin immunoprecipitation sequencing of dimethylated histone 3 lysine 4 and acetylated histone 3 lysine 27 as well as transposase-accessible chromatin profiling to dissect cis-regulatory networks across muscle groups. We demonstrate that in vivo enhancers specify muscles in accordance with myofiber composition, show little resemblance to cultured myotube enhancers, and identify glycolytic and oxidative muscle-specific regulators. Moreover, we find that voluntary wheel running and muscle-specific peroxisome proliferator–activated receptor gamma coactivator-1 alpha (Pgc1a) transgenic (mTg) overexpression, which stimulate endurance performance in mice, result in markedly different changes to the epigenome. Exercise predominantly leads to enhancer hypoacetylation, whereas mTg causes hyperacetylation at different sites. Integrative analysis of regulatory regions and gene expression revealed that exercise and mTg are each associated with myocyte enhancer factor (MEF) 2 and estrogen-related receptor (ERR) signaling and transcription of genes promoting oxidative metabolism. However, exercise was additionally associated with regulation by retinoid X receptor (RXR), jun proto-oncogene (JUN), sine oculis homeobox factor (SIX), and other factors. Overall, our work defines the unique enhancer repertoires of skeletal muscles in vivo and reveals that divergent exercise-induced or PGC1α-driven epigenomic programs direct partially convergent transcriptional networks.
AB - Skeletal muscles consist of fibers of differing metabolic activities and contractility, which become remodeled in response to chronic exercise, but the epigenomic basis for muscle identity and adaptation remains poorly understood. Here, we used chromatin immunoprecipitation sequencing of dimethylated histone 3 lysine 4 and acetylated histone 3 lysine 27 as well as transposase-accessible chromatin profiling to dissect cis-regulatory networks across muscle groups. We demonstrate that in vivo enhancers specify muscles in accordance with myofiber composition, show little resemblance to cultured myotube enhancers, and identify glycolytic and oxidative muscle-specific regulators. Moreover, we find that voluntary wheel running and muscle-specific peroxisome proliferator–activated receptor gamma coactivator-1 alpha (Pgc1a) transgenic (mTg) overexpression, which stimulate endurance performance in mice, result in markedly different changes to the epigenome. Exercise predominantly leads to enhancer hypoacetylation, whereas mTg causes hyperacetylation at different sites. Integrative analysis of regulatory regions and gene expression revealed that exercise and mTg are each associated with myocyte enhancer factor (MEF) 2 and estrogen-related receptor (ERR) signaling and transcription of genes promoting oxidative metabolism. However, exercise was additionally associated with regulation by retinoid X receptor (RXR), jun proto-oncogene (JUN), sine oculis homeobox factor (SIX), and other factors. Overall, our work defines the unique enhancer repertoires of skeletal muscles in vivo and reveals that divergent exercise-induced or PGC1α-driven epigenomic programs direct partially convergent transcriptional networks.
UR - http://www.scopus.com/inward/record.url?scp=85073575592&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85073575592&partnerID=8YFLogxK
U2 - 10.1371/journal.pbio.3000467
DO - 10.1371/journal.pbio.3000467
M3 - Article
C2 - 31589602
AN - SCOPUS:85073575592
VL - 17
JO - PLoS Biology
JF - PLoS Biology
SN - 1544-9173
IS - 10
M1 - e3000467
ER -