Multi-omic identification of key transcriptional regulatory programs during endurance exercise training in rats

Transcription factors play a key role in regulating gene expression. We conduct an integrated analysis of chromatin accessibility, DNA methylation, mRNA expression, protein abundance and phosphorylation across eight tissues in fifty rats of equally represented sexes following endurance exercise training to identify coordinated epigenomic and transcriptional changes and determine key transcription factors involved. We uncover tissue-specific endurance exercise training associated changes and transcription factor motif enrichment across differentially expressed genes, accessible regions, and methylated regions. We discover distinct routes of training-induced regulation through either epigenomic alterations providing better access for transcription factors to affect target genes, or via changes in transcription factor expression or activity enabling target gene responses. We identify transcription factor motifs enriched among correlated epigenomic and transcriptomic alterations, differentially expressed genes correlated with exercise-related phenotypic and cell type composition changes, and training-induced activity changes of transcription factors whose target genes are enriched for differentially expressed genes. This analysis elucidates the unique gene regulatory mechanisms mediating diverse transcriptional responses to training across tissues.

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Journal
Nature Communications
Published
2026-03-21
DOI
https://doi.org/10.1038/s41467-026-70397-0
Primary Topic
Genetics and Physical Performance
Type
article
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article

Multi-omic identification of key transcriptional regulatory programs during endurance exercise training in rats

Sindhu Vangeti, Clarisa Chavez, Navid Zebarjadi, Alexandria Vornholt et al.
Nature Communications
Genetics and Physical Performance
article

Multi-omic identification of key transcriptional regulatory programs during endurance exercise training in rats

Sindhu Vangeti, Clarisa Chavez, Navid Zebarjadi, Alexandria Vornholt, Elisabeth R. Barton, Bridget Lester, Chongzhi Zang, Blake B. Rasmussen, Paul Piehowski, Brent G. Albertson, Aliza B. Rubenstein, David A. Gaul, Andrea Lynn Hevener, Collyn Z-T. Richards, Bailey E. Jackson, Nitish Seenarine, Karan Uppal, Zhenxin Hou, Stas Rirak, Chelsea Hutchinson-Bunch, Nathan Makarewicz, Mital Vasoya, Krista M. Hennig, Elena Zaslavsky, Julián Ávila-Pacheco, Shruti Marwaha, Nasim Bararpour, Maria D. Chikina, Kishore M. Gadde, Alec Steep, Sandy May, Christopher Teng, Catherine M. Jankowski, Bingqing Zhao, Mihir Samdarshi, Eric Ravussin, Elaine Cornell, Frederique Ruf-Zamojski, Michael Z. Cicha, Facundo M. Fernández, Jessica L. Rooney, Fang‐Chi Hsu, Eric A. Ortlund, Hasmik Keshishian, Trevor Hastie, Steven G. Hershman, Luís Gustavo Oliveira de Sousa, Mary Anne S. Amper, Tiantian Zhang, Irene Ramos, Toby L. Chambers, Nicole Gagne, SURENDRA DASARI, Chia-Jui Hung, Karen Dalton, Samuel G. Moore, Marcas M. Bamman, Kristal Maner-Smith, Nicole R. Gay, Michael P. Walkup, Nada Marjanović, Yue Ge, Kristy Guevara, Kerrie L. Moreau, Tiziana Caputo, Benjamin G. Ke, David M. Presby, Daniel Nachun, Maureen T. Kachman, Charles R. Evans, Brian Bouverat, Tyler J. Sagendorf, Marina Gritsenko, Jimmy Zhen, Gina M. Many, Dam Bae, Nikolai G. Vetr, Cynthia L. Stowe, Michael Nestor, Megan E. Ramaker, Ian R. Lanza, Bryan C. Bergman, Roger P. Farrar, Xueyun Liu, Neil M. Johannsen, Evan Savage, Joshua Adkins, David Jimenez-Morales, Kevin Smith, Cadence Pearce, Fadia Haddad, Robert S. Schwartz, Ching-ju Lu, Rob Tibshirani, Roxanne Chiu, Ali Tugrul Balci, Matthew Monroe, Hanna Pincas, Zhen Yan, Christopher A. Jin, Anna A. Ivanova, Kyle S. Kramer, W. Jack Rejeski, John P. Williams, D. R. Mani, K. Sreekumaran Nair, Vladislav A. Petyuk, Christiaan Leeuwenburgh, Todd A. Trappe, Matthew T. Wheeler, Elena Volpi, German Nudelman, Irene E. Schauer, Alexander Sasha Raskind, Malene E. Lindholm, Simon Schenk, Steven Carr, Nicolas Musi, Frank W. Booth, for the MoTrPAC Study Group, Scott Powers, Archana Natarajan Raja, Sue C. Bodine, Andrea Marshall, James A. Sanford, Paul M. Coen, Wei-Jun Qian, William E. Kraus, Melissa Harris, Jeremy M. Robbins, Laurie J. Goodyear, Thomas W. Buford, Shlomit Radom-Aizik, Robert L. Newton, Russell Tracy, Jose Juan Almagro Armenteros, Ronald J. Moore, Yifei Sun, Daniel H. Bessesen, Pasquale Nigro, Stuart C. Sealfon, Jun Z. Li, Courtney Dennis, Euan Ashley, Robert E. Gerszten, Karyn A. Esser, Tanu Soni, Xuechen Yu, Stephen B. Montgomery, Tuomo Rankinen, Michael F. Hirshman, Ashley Xia, Venugopalan D. Nair, Bret H. Goodpaster, Dan Cooper, Wendy M. Kohrt, Ana K. Lira, Michael P. Snyder, Marco Pahor, Gregory R. Smith, Martin J. Walsh, Michael E. Miller, David Amar, John Thyfault, Edward L. Melanson, Si Wu, Joshua R. Hansen, Sarah J. Lessard, Pierre M. Jean Beltran, Anna Thalacker-Mercer, Krithika Ramachandran, Lauren M. Sparks, Charles F. Burant, Scott Rushing, Clary B. Clish, Charles C. Mundorff, Scott Trappe, R. Scott Rector, Gary Cutter, Mark Viggars, Barbara Nicklas, Kim M. Huffman
article en

Abstract

Transcription factors play a key role in regulating gene expression. We conduct an integrated analysis of chromatin accessibility, DNA methylation, mRNA expression, protein abundance and phosphorylation across eight tissues in fifty rats of equally represented sexes following endurance exercise training to identify coordinated epigenomic and transcriptional changes and determine key transcription factors involved. We uncover tissue-specific endurance exercise training associated changes and transcription factor motif enrichment across differentially expressed genes, accessible regions, and methylated regions. We discover distinct routes of training-induced regulation through either epigenomic alterations providing better access for transcription factors to affect target genes, or via changes in transcription factor expression or activity enabling target gene responses. We identify transcription factor motifs enriched among correlated epigenomic and transcriptomic alterations, differentially expressed genes correlated with exercise-related phenotypic and cell type composition changes, and training-induced activity changes of transcription factors whose target genes are enriched for differentially expressed genes. This analysis elucidates the unique gene regulatory mechanisms mediating diverse transcriptional responses to training across tissues.

Nature Communications
Pennington Biomedical Research Center (US), Broad Institute (US), University of Vermont (US), University of Iowa (US), Joslin Diabetes Center (US), National Institutes of Health (US), Georgia Institute of Technology (US), Pacific Northwest National Laboratory (US), Emory University (US), University of California, Los Angeles (US), The University of Texas at San Antonio Health Science Center (US), University of Pittsburgh (US), Duke University (US), Ball State University (US), University of California, Irvine (US), University of Michigan (US), University of Alabama at Birmingham (US), University of Florida (US), Mayo Clinic in Arizona (US), University of Kansas Medical Center (US), Wenner-Gren Foundations (SE), Translational Research Institute for Metabolism and Diabetes (US), Stanford Medicine (US), Wake Forest University (US), University of Virginia (US), University of Colorado Anschutz Medical Campus (US), The University of Texas Medical Branch at Galveston (US), University of Missouri (US), Stanford University (US), Icahn School of Medicine at Mount Sinai (US)
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