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1. The impact of exercise on gene regulation in association with complex trait genetics

Author

Vetr, Nikolai G, Gay, Nicole R, and Montgomery, Stephen B

Subjects
Biological Sciences, Health Sciences, Genetics, Sports Science and Exercise, Prevention, Physical Activity, 2.1 Biological and endogenous factors, Animals, Humans, Physical Conditioning, Animal, Rats, Gene Expression Regulation, Transcriptome, Multifactorial Inheritance, Exercise, Male, Phenotype, Quantitative Trait Loci, Gene Expression Profiling, MoTrPAC Study Group
Abstract

Endurance exercise training is known to reduce risk for a range of complex diseases. However, the molecular basis of this effect has been challenging to study and largely restricted to analyses of either few or easily biopsied tissues. Extensive transcriptome data collected across 15 tissues during exercise training in rats as part of the Molecular Transducers of Physical Activity Consortium has provided a unique opportunity to clarify how exercise can affect tissue-specific gene expression and further suggest how exercise adaptation may impact complex disease-associated genes. To build this map, we integrate this multi-tissue atlas of gene expression changes with gene-disease targets, genetic regulation of expression, and trait relationship data in humans. Consensus from multiple approaches prioritizes specific tissues and genes where endurance exercise impacts disease-relevant gene expression. Specifically, we identify a total of 5523 trait-tissue-gene triplets to serve as a valuable starting point for future investigations [Exercise; Transcription; Human Phenotypic Variation].

Published
2024

2. Sexual dimorphism and the multi-omic response to exercise training in rat subcutaneous white adipose tissue

Author

Many, Gina M, Sanford, James A, Sagendorf, Tyler J, Hou, Zhenxin, Nigro, Pasquale, Whytock, Katie L, Amar, David, Caputo, Tiziana, Gay, Nicole R, Gaul, David A, Hirshman, Michael F, Jimenez-Morales, David, Lindholm, Malene E, Muehlbauer, Michael J, Vamvini, Maria, Bergman, Bryan C, Fernández, Facundo M, Goodyear, Laurie J, Hevener, Andrea L, Ortlund, Eric A, Sparks, Lauren M, Xia, Ashley, Adkins, Joshua N, Bodine, Sue C, Newgard, Christopher B, and Schenk, Simon

Subjects
Medical Biochemistry and Metabolomics, Medical Physiology, Biomedical and Clinical Sciences, Nutrition and Dietetics, Physical Activity, Women's Health, Prevention, Behavioral and Social Science, Animals, Male, Female, Physical Conditioning, Animal, Rats, Sex Characteristics, Adipose Tissue, White, Subcutaneous Fat, Adipogenesis, Rats, Sprague-Dawley, Multiomics, MoTrPAC Study Group, Medical biochemistry and metabolomics, Medical physiology, Nutrition and dietetics
Abstract

Subcutaneous white adipose tissue (scWAT) is a dynamic storage and secretory organ that regulates systemic homeostasis, yet the impact of endurance exercise training (ExT) and sex on its molecular landscape is not fully established. Utilizing an integrative multi-omics approach, and leveraging data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we show profound sexual dimorphism in the scWAT of sedentary rats and in the dynamic response of this tissue to ExT. Specifically, the scWAT of sedentary females displays -omic signatures related to insulin signaling and adipogenesis, whereas the scWAT of sedentary males is enriched in terms related to aerobic metabolism. These sex-specific -omic signatures are preserved or amplified with ExT. Integration of multi-omic analyses with phenotypic measures identifies molecular hubs predicted to drive sexually distinct responses to training. Overall, this study underscores the powerful impact of sex on adipose tissue biology and provides a rich resource to investigate the scWAT response to ExT.

Published
2024

3. Molecular adaptations in response to exercise training are associated with tissue-specific transcriptomic and epigenomic signatures

Author

Adkins, Joshua N., Almagro Armenteros, Jose Juan, Ashley, Euan, Bae, Dam, Bamman, Marcas, Bararpour, Nasim, Bennett, Alexis, Bergman, Bryan C., Bessesen, Daniel H., Bodine, Sue C., Buford, Thomas W., Chambers, Toby L., Chavez, Clarisa, Cortes, Tiffany, Cutter, Gary, Espinoza, Sara, Fernández, Facundo M., Gagne, Nicole, Gaul, David A., Goodpaster, Bret H., Hung, Chia-Jui, Jackson, Bailey E., Jankowski, Catherine M., Jin, Christopher A., Kohrt, Wendy M., Kramer, Kyle S., Lester, Bridget, Lira, Ana K., May, Sandy, Marjanovic, Nada, Melanson, Edward L., Moore, Samuel G., Moreau, Kerrie L., Musi, Nicolas, Nachum, Daniel, Nudelman, German, Pahor, Marco, Patel, Darpan, Piehowski, Paul D., Qian, Wei-Jun, Rasmussen, Blake B., Rirak, Stas, Rooney, Jessica L., Sanford, James A., Savage, Evan M., Schauer, Irene E., Serra, Monica, Stowe, Cynthia L., Thalacker-Mercer, Anna, Trappe, Todd A., Trappe, Scott, Vetr, Nikolai G., Volpi, Elena, Wheeler, Matthew T., Wu, Si, Zebarjadi, Navid, Zhen, Jimmy, Nair, Venugopalan D., Pincas, Hanna, Smith, Gregory R., Zaslavsky, Elena, Ge, Yongchao, Amper, Mary Anne S., Vasoya, Mital, Chikina, Maria, Sun, Yifei, Raja, Archana Natarajan, Mao, Weiguang, Gay, Nicole R., Esser, Karyn A., Smith, Kevin S., Zhao, Bingqing, Wiel, Laurens, Singh, Aditya, Lindholm, Malene E., Amar, David, Montgomery, Stephen, Snyder, Michael P., Walsh, Martin J., and Sealfon, Stuart C.

Published
2024
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4. The mitochondrial multi-omic response to exercise training across rat tissues

Author

Adkins, Joshua N., Armenteros, Jose Juan Almagro, Amper, Mary Anne S., Bae, Dam, Bamman, Marcas, Bararpour, Nasim, Barnes, Jerry, Bergman, Bryan C., Bessesen, Daniel H., Broskey, Nicholas T., Buford, Thomas W., Carr, Steven, Chambers, Toby L., Chavez, Clarisa, Chiu, Roxanne, Clark, Natalie, Cutter, Gary, Evans, Charles R., Franczak, Edziu, Gagne, Nicole, Ge, Yongchao, Hennig, Krista M., Houmard, Joseph A., Huffman, Kim M., Hung, Chia-Jui, Hutchinson-Bunch, Chelsea, Ilkayeva, Olga, Jackson, Bailey E., Jankowski, Catherine M., Jin, Christopher A., Johannsen, Neil M., Katz, Daniel H., Keshishian, Hasmik, Kohrt, Wendy M., Kramer, Kyle S., Kraus, William E., Lester, Bridget, Li, Jun Z., Lira, Ana K., Lowe, Adam, Mani, D.R., Many, Gina M., May, Sandy, Melanson, Edward L., Moore, Samuel G., Moreau, Kerrie L., Musi, Nicolas, Nachun, Daniel, Nair, Venugopalan D., Newgard, Christopher, Nudelman, German, Piehowski, Paul D., Pincas, Hanna, Qian, Wei-Jun, Rankinen, Tuomo, Rasmussen, Blake B., Ravussin, Eric, Rooney, Jessica L., Rushing, Scott, Samdarshi, Mihir, Sanford, James A., Schauer, Irene E., Sealfon, Stuart C., Smith, Kevin S., Smith, Gregory R., Snyder, Michael, Stowe, Cynthia L., Talton, Jennifer W., Teng, Christopher, Thalacker-Mercer, Anna, Tracy, Russell, Trappe, Scott, Trappe, Todd A., Vasoya, Mital, Vetr, Nikolai G., Volpi, Elena, Walkup, Michael P., Wiel, Laurens, Wu, Si, Yan, Zhen, Yu, Jiye, Zaslavsky, Elena, Zebarjadi, Navid, Zhen, Jimmy, Amar, David, Gay, Nicole R., Jimenez-Morales, David, Jean Beltran, Pierre M., Ramaker, Megan E., Raja, Archana Natarajan, Zhao, Bingqing, Sun, Yifei, Marwaha, Shruti, Gaul, David A., Hershman, Steven G., Ferrasse, Alexis, Xia, Ashley, Lanza, Ian, Fernández, Facundo M., Montgomery, Stephen B., Hevener, Andrea L., Ashley, Euan A., Walsh, Martin J., Sparks, Lauren M., Burant, Charles F., Rector, R. Scott, Thyfault, John, Wheeler, Matthew T., Goodpaster, Bret H., Coen, Paul M., Schenk, Simon, Bodine, Sue C., and Lindholm, Malene E.

Published
2024
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6. Molecular adaptations in response to exercise training are associated with tissue-specific transcriptomic and epigenomic signatures

Author

Nair, Venugopalan D., primary, Pincas, Hanna, additional, Smith, Gregory R., additional, Zaslavsky, Elena, additional, Ge, Yongchao, additional, Amper, Mary Anne S., additional, Vasoya, Mital, additional, Chikina, Maria, additional, Sun, Yifei, additional, Raja, Archana Natarajan, additional, Mao, Weiguang, additional, Gay, Nicole R., additional, Esser, Karyn A., additional, Smith, Kevin S., additional, Zhao, Bingqing, additional, Wiel, Laurens, additional, Singh, Aditya, additional, Lindholm, Malene E., additional, Amar, David, additional, Montgomery, Stephen, additional, Snyder, Michael P., additional, Walsh, Martin J., additional, and Sealfon, Stuart C., additional

Published
2024
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7. Sexual dimorphism and the multi-omic response to exercise training in rat subcutaneous white adipose tissue

Author

Many, Gina M, primary, Sanford, James A, additional, Sagendorf, Tyler J, additional, Hou, Zhenxin, additional, Nigro, Pasquale, additional, Whytock, Katie L, additional, Amar, David, additional, Caputo, Tiziana, additional, Gay, Nicole R, additional, Gaul, David A, additional, Hirshman, Michael F, additional, Jimenez-Morales, David, additional, Lindholm, Malene E, additional, Muehlbauer, Michael J, additional, Vamvini, Maria, additional, Bergman, Bryan C, additional, Fernandez, Facundo M, additional, Goodyear, Laurie J, additional, Ortlund, Eric A, additional, Sparks, Lauren M, additional, Xia, Ashley, additional, Adkins, Joshua N, additional, Bodine, Sue C, additional, Newgard, Christopher B, additional, Schenk, Simon, additional, and Study Group, The MoTrPAC, additional

Published
2023
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8. Sexual dimorphism and the multi-omic response to exercise training in rat subcutaneous white adipose tissue

Author

Many, Gina M., Sanford, James A., Sagendorf, Tyler J., Hou, Zhenxin, Nigro, Pasquale, Whytock, Katie, Amar, David, Caputo, Tiziana, Gay, Nicole R., Gaul, David A., Hirshman, Michael, Jimenez-Morales, David, Lindholm, Malene E., Muehlbauer, Michael J., Vamvini, Maria, Bergman, Bryan, Fern√°ndez, Facundo M., Goodyear, Laurie J., Ortlund, Eric A., Sparks, Lauren M., Xia, Ashley, Adkins, Joshua N., Bodine, Sue C., Newgard, Christopher B., and Schenk, Simon

Subjects
Article
Abstract

Subcutaneous white adipose tissue (scWAT) is a dynamic storage and secretory organ that regulates systemic homeostasis, yet the impact of endurance exercise training and sex on its molecular landscape has not been fully established. Utilizing an integrative multi-omics approach with data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we identified profound sexual dimorphism in the dynamic response of rat scWAT to endurance exercise training. Despite similar cardiorespiratory improvements, only male rats reduced whole-body adiposity, scWAT adipocyte size, and total scWAT triglyceride abundance with training. Multi-omic analyses of adipose tissue integrated with phenotypic measures identified sex-specific training responses including enrichment of mTOR signaling in females, while males displayed enhanced mitochondrial ribosome biogenesis and oxidative metabolism. Overall, this study reinforces our understanding that sex impacts scWAT biology and provides a rich resource to interrogate responses of scWAT to endurance training.

Published
2023

9. Multiomic identification of key transcriptional regulatory programs during endurance exercise training

Author

Smith, Gregory R., Zhao, Bingqing, Lindholm, Malene E., Raja, Archana, Viggars, Mark, Pincas, Hanna, Gay, Nicole R., Sun, Yifei, Ge, Yongchao, Nair, Venugopalan D., Sanford, James A., S. Amper, Mary Anne, Vasoya, Mital, Smith, Kevin S., Montgomery, Stephen, Zaslavsky, Elena, Bodine, Sue C., Esser, Karyn A., Walsh, Martin J., Snyder, Michael P., and Sealfon, Stuart C.

Subjects
Article
Abstract

Transcription factors (TFs) play a key role in regulating gene expression and responses to stimuli. We conducted an integrated analysis of chromatin accessibility and RNA expression across various rat tissues following endurance exercise training (EET) to map epigenomic changes to transcriptional changes and determine key TFs involved. We uncovered tissue-specific changes across both omic layers, including highly correlated differentially accessible regions (DARs) and differentially expressed genes (DEGs). We identified open chromatin regions associated with DEGs (DEGaPs) and found tissue-specific and genomic feature-specific TF motif enrichment patterns among both DARs and DEGaPs. Accessible promoters of up-vs. down-regulated DEGs per tissue showed distinct TF enrichment patterns. Further, some EET-induced TFs in skeletal muscle were either validated at the proteomic level (MEF2C and NUR77) or correlated with exercise-related phenotypic changes. We provide an in-depth analysis of the epigenetic and trans-factor-dependent processes governing gene expression during EET.

Published
2023

10. Population-scale tissue transcriptomics maps long non-coding RNAs to complex disease

Author

de Goede, Olivia M., primary, Nachun, Daniel C., additional, Ferraro, Nicole M., additional, Gloudemans, Michael J., additional, Rao, Abhiram S., additional, Smail, Craig, additional, Eulalio, Tiffany Y., additional, Aguet, François, additional, Ng, Bernard, additional, Xu, Jishu, additional, Barbeira, Alvaro N., additional, Castel, Stephane E., additional, Kim-Hellmuth, Sarah, additional, Park, YoSon, additional, Scott, Alexandra J., additional, Strober, Benjamin J., additional, Brown, Christopher D., additional, Wen, Xiaoquan, additional, Hall, Ira M., additional, Battle, Alexis, additional, Lappalainen, Tuuli, additional, Im, Hae Kyung, additional, Ardlie, Kristin G., additional, Mostafavi, Sara, additional, Quertermous, Thomas, additional, Kirkegaard, Karla, additional, Montgomery, Stephen B., additional, Anand, Shankara, additional, Gabriel, Stacey, additional, Getz, Gad A., additional, Graubert, Aaron, additional, Hadley, Kane, additional, Handsaker, Robert E., additional, Huang, Katherine H., additional, Li, Xiao, additional, MacArthur, Daniel G., additional, Meier, Samuel R., additional, Nedzel, Jared L., additional, Nguyen, Duyen T., additional, Segrè, Ayellet V., additional, Todres, Ellen, additional, Balliu, Brunilda, additional, Bonazzola, Rodrigo, additional, Brown, Andrew, additional, Conrad, Donald F., additional, Cotter, Daniel J., additional, Cox, Nancy, additional, Das, Sayantan, additional, Dermitzakis, Emmanouil T., additional, Einson, Jonah, additional, Engelhardt, Barbara E., additional, Eskin, Eleazar, additional, Flynn, Elise D., additional, Fresard, Laure, additional, Gamazon, Eric R., additional, Garrido-Martín, Diego, additional, Gay, Nicole R., additional, Guigó, Roderic, additional, Hamel, Andrew R., additional, He, Yuan, additional, Hoffman, Paul J., additional, Hormozdiari, Farhad, additional, Hou, Lei, additional, Jo, Brian, additional, Kasela, Silva, additional, Kashin, Seva, additional, Kellis, Manolis, additional, Kwong, Alan, additional, Li, Xin, additional, Liang, Yanyu, additional, Mangul, Serghei, additional, Mohammadi, Pejman, additional, Muñoz-Aguirre, Manuel, additional, Nobel, Andrew B., additional, Oliva, Meritxell, additional, Park, Yongjin, additional, Parsana, Princy, additional, Reverter, Ferran, additional, Rouhana, John M., additional, Sabatti, Chiara, additional, Saha, Ashis, additional, Stephens, Matthew, additional, Stranger, Barbara E., additional, Teran, Nicole A., additional, Viñuela, Ana, additional, Wang, Gao, additional, Wright, Fred, additional, Wucher, Valentin, additional, Zou, Yuxin, additional, Ferreira, Pedro G., additional, Li, Gen, additional, Melé, Marta, additional, Yeger-Lotem, Esti, additional, Bradbury, Debra, additional, Krubit, Tanya, additional, McLean, Jeffrey A., additional, Qi, Liqun, additional, Robinson, Karna, additional, Roche, Nancy V., additional, Smith, Anna M., additional, Tabor, David E., additional, Undale, Anita, additional, Bridge, Jason, additional, Brigham, Lori E., additional, Foster, Barbara A., additional, Gillard, Bryan M., additional, Hasz, Richard, additional, Hunter, Marcus, additional, Johns, Christopher, additional, Johnson, Mark, additional, Karasik, Ellen, additional, Kopen, Gene, additional, Leinweber, William F., additional, McDonald, Alisa, additional, Moser, Michael T., additional, Myer, Kevin, additional, Ramsey, Kimberley D., additional, Roe, Brian, additional, Shad, Saboor, additional, Thomas, Jeffrey A., additional, Walters, Gary, additional, Washington, Michael, additional, Wheeler, Joseph, additional, Jewell, Scott D., additional, Rohrer, Daniel C., additional, Valley, Dana R., additional, Davis, David A., additional, Mash, Deborah C., additional, Barcus, Mary E., additional, Branton, Philip A., additional, Sobin, Leslie, additional, Barker, Laura K., additional, Gardiner, Heather M., additional, Mosavel, Maghboeba, additional, Siminoff, Laura A., additional, Flicek, Paul, additional, Haeussler, Maximilian, additional, Juettemann, Thomas, additional, Kent, W. James, additional, Lee, Christopher M., additional, Powell, Conner C., additional, Rosenbloom, Kate R., additional, Ruffier, Magali, additional, Sheppard, Dan, additional, Taylor, Kieron, additional, Trevanion, Stephen J., additional, Zerbino, Daniel R., additional, Abell, Nathan S., additional, Akey, Joshua, additional, Chen, Lin, additional, Demanelis, Kathryn, additional, Doherty, Jennifer A., additional, Feinberg, Andrew P., additional, Hansen, Kasper D., additional, Hickey, Peter F., additional, Jasmine, Farzana, additional, Jiang, Lihua, additional, Kaul, Rajinder, additional, Kibriya, Muhammad G., additional, Li, Jin Billy, additional, Li, Qin, additional, Lin, Shin, additional, Linder, Sandra E., additional, Pierce, Brandon L., additional, Rizzardi, Lindsay F., additional, Skol, Andrew D., additional, Smith, Kevin S., additional, Snyder, Michael, additional, Stamatoyannopoulos, John, additional, Tang, Hua, additional, Wang, Meng, additional, Carithers, Latarsha J., additional, Guan, Ping, additional, Koester, Susan E., additional, Little, A. Roger, additional, Moore, Helen M., additional, Nierras, Concepcion R., additional, Rao, Abhi K., additional, Vaught, Jimmie B., additional, and Volpi, Simona, additional

Published
2021
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11. Additional file 10 of Impact of admixture and ancestry on eQTL analysis and GWAS colocalization in GTEx

Author

Gay, Nicole R., Gloudemans, Michael, Antonio, Margaret L., Abell, Nathan S., Balliu, Brunilda, YoSon Park, Martin, Alicia R., Musharoff, Shaila, Abhiram S. Rao, Aguet, François, Barbeira, Alvaro N., Bonazzola, Rodrigo, Hormozdiari, Farhad, Ardlie, Kristin G., Brown, Christopher D., Im, Hae Kyung, Lappalainen, Tuuli, Xiaoquan Wen, and Montgomery, Stephen B.

Abstract

Additional file 10. Review History.

Published
2020
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12. The mitochondrial multi-omic response to exercise training across rat tissues.

Author

Amar, David, Gay, Nicole R., Jimenez-Morales, David, Jean Beltran, Pierre M., Ramaker, Megan E., Raja, Archana Natarajan, Zhao, Bingqing, Sun, Yifei, Marwaha, Shruti, Gaul, David A., Hershman, Steven G., Ferrasse, Alexis, Xia, Ashley, Lanza, Ian, Fernández, Facundo M., Montgomery, Stephen B., Hevener, Andrea L., Ashley, Euan A., Walsh, Martin J., and Sparks, Lauren M.

Abstract

Mitochondria have diverse functions critical to whole-body metabolic homeostasis. Endurance training alters mitochondrial activity, but systematic characterization of these adaptations is lacking. Here, the Molecular Transducers of Physical Activity Consortium mapped the temporal, multi-omic changes in mitochondrial analytes across 19 tissues in male and female rats trained for 1, 2, 4, or 8 weeks. Training elicited substantial changes in the adrenal gland, brown adipose, colon, heart, and skeletal muscle. The colon showed non-linear response dynamics, whereas mitochondrial pathways were downregulated in brown adipose and adrenal tissues. Protein acetylation increased in the liver, with a shift in lipid metabolism, whereas oxidative proteins increased in striated muscles. Exercise-upregulated networks were downregulated in human diabetes and cirrhosis. Knockdown of the central network protein 17-beta-hydroxysteroid dehydrogenase 10 (HSD17B10) elevated oxygen consumption, indicative of metabolic stress. We provide a multi-omic, multi-tissue, temporal atlas of the mitochondrial response to exercise training and identify candidates linked to mitochondrial dysfunction. [Display omitted] • Multi-omic atlas of the mitochondrial response to exercise training in 19 rat tissues • Robust temporal differences in mitochondrial response by -omes, tissues, and sex • Most dynamic responses in adrenal, brown adipose, colon, heart, liver, and muscle • Protein networks upregulated by exercise are downregulated in human T2D and cirrhosis Amar et al. delineate the extensive molecular modifications occurring in mitochondria, central metabolic organelles, in response to endurance exercise training across diverse rat tissues. Their translational analysis suggests clinical relevance of the metabolic regulator HSD17B10. Its suppression induces metabolic stress in liver cells, underlining its potential role in disease pathology. [ABSTRACT FROM AUTHOR]

Published
2024
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13. A Quantitative Proteome Map of the Human Body

Author

Jiang, Lihua, primary, Wang, Meng, additional, Lin, Shin, additional, Jian, Ruiqi, additional, Li, Xiao, additional, Chan, Joanne, additional, Dong, Guanlan, additional, Fang, Huaying, additional, Robinson, Aaron E., additional, Snyder, Michael P., additional, Aguet, François, additional, Anand, Shankara, additional, Ardlie, Kristin G., additional, Gabriel, Stacey, additional, Getz, Gad, additional, Graubert, Aaron, additional, Hadley, Kane, additional, Handsaker, Robert E., additional, Huang, Katherine H., additional, Kashin, Seva, additional, MacArthur, Daniel G., additional, Meier, Samuel R., additional, Nedzel, Jared L., additional, Nguyen, Duyen Y., additional, Segrè, Ayellet V., additional, Todres, Ellen, additional, Balliu, Brunilda, additional, Barbeira, Alvaro N., additional, Battle, Alexis, additional, Bonazzola, Rodrigo, additional, Brown, Andrew, additional, Brown, Christopher D., additional, Castel, Stephane E., additional, Conrad, Don, additional, Cotter, Daniel J., additional, Cox, Nancy, additional, Das, Sayantan, additional, de Goede, Olivia M., additional, Dermitzakis, Emmanouil T., additional, Engelhardt, Barbara E., additional, Eskin, Eleazar, additional, Eulalio, Tiffany Y., additional, Ferraro, Nicole M., additional, Flynn, Elise, additional, Fresard, Laure, additional, Gamazon, Eric R., additional, Garrido-Martín, Diego, additional, Gay, Nicole R., additional, Guigó, Roderic, additional, Hamel, Andrew R., additional, He, Yuan, additional, Hoffman, Paul J., additional, Hormozdiari, Farhad, additional, Hou, Lei, additional, Im, Hae Kyung, additional, Jo, Brian, additional, Kasela, Silva, additional, Kellis, Manolis, additional, Kim-Hellmuth, Sarah, additional, Kwong, Alan, additional, Lappalainen, Tuuli, additional, Li, Xin, additional, Liang, Yanyu, additional, Mangul, Serghei, additional, Mohammadi, Pejman, additional, Montgomery, Stephen B., additional, Muñoz-Aguirre, Manuel, additional, Nachun, Daniel C., additional, Nobel, Andrew B., additional, Oliva, Meritxell, additional, Park, YoSon, additional, Park, Yongjin, additional, Parsana, Princy, additional, Reverter, Ferran, additional, Rouhana, John M., additional, Sabatti, Chiara, additional, Saha, Ashis, additional, Skol, Andrew D., additional, Stephens, Matthew, additional, Stranger, Barbara E., additional, Strober, Benjamin J., additional, Teran, Nicole A., additional, Viñuela, Ana, additional, Wang, Gao, additional, Wen, Xiaoquan, additional, Wright, Fred, additional, Wucher, Valentin, additional, Zou, Yuxin, additional, Ferreira, Pedro G., additional, Li, Gen, additional, Melé, Marta, additional, Yeger-Lotem, Esti, additional, Barcus, Mary E., additional, Bradbury, Debra, additional, Krubit, Tanya, additional, McLean, Jeffrey A., additional, Qi, Liqun, additional, Robinson, Karna, additional, Roche, Nancy V., additional, Smith, Anna M., additional, Sobin, Leslie, additional, Tabor, David E., additional, Undale, Anita, additional, Bridge, Jason, additional, Brigham, Lori E., additional, Foster, Barbara A., additional, Gillard, Bryan M., additional, Hasz, Richard, additional, Hunter, Marcus, additional, Johns, Christopher, additional, Johnson, Mark, additional, Karasik, Ellen, additional, Kopen, Gene, additional, Leinweber, William F., additional, McDonald, Alisa, additional, Moser, Michael T., additional, Myer, Kevin, additional, Ramsey, Kimberley D., additional, Roe, Brian, additional, Shad, Saboor, additional, Thomas, Jeffrey A., additional, Walters, Gary, additional, Washington, Michael, additional, Wheeler, Joseph, additional, Jewell, Scott D., additional, Rohrer, Daniel C., additional, Valley, Dana R., additional, Davis, David A., additional, Mash, Deborah C., additional, Branton, Philip A., additional, Barker, Laura K., additional, Gardiner, Heather M., additional, Mosavel, Maghboeba, additional, Siminoff, Laura A., additional, Flicek, Paul, additional, Haeussler, Maximilian, additional, Juettemann, Thomas, additional, Kent, W. James, additional, Lee, Christopher M., additional, Powell, Conner C., additional, Rosenbloom, Kate R., additional, Ruffier, Magali, additional, Sheppard, Dan, additional, Taylor, Kieron, additional, Trevanion, Stephen J., additional, Zerbino, Daniel R., additional, Abell, Nathan S., additional, Akey, Joshua, additional, Chen, Lin, additional, Demanelis, Kathryn, additional, Doherty, Jennifer A., additional, Feinberg, Andrew P., additional, Hansen, Kasper D., additional, Hickey, Peter F., additional, Jasmine, Farzana, additional, Kaul, Rajinder, additional, Kibriya, Muhammad G., additional, Li, Jin Billy, additional, Li, Qin, additional, Linder, Sandra E., additional, Pierce, Brandon L., additional, Rizzardi, Lindsay F., additional, Smith, Kevin S., additional, Stamatoyannopoulos, John, additional, Tang, Hua, additional, Carithers, Latarsha J., additional, Guan, Ping, additional, Koester, Susan E., additional, Little, A. Roger, additional, Moore, Helen M., additional, Nierras, Concepcion R., additional, Rao, Abhi K., additional, Vaught, Jimmie B., additional, and Volpi, Simona, additional

Published
2020
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14. Molecular Transducers of Physical Activity Consortium (MoTrPAC): Mapping the Dynamic Responses to Exercise

Author

Sanford, James A., primary, Nogiec, Christopher D., additional, Lindholm, Malene E., additional, Adkins, Joshua N., additional, Amar, David, additional, Dasari, Surendra, additional, Drugan, Jonelle K., additional, Fernández, Facundo M., additional, Radom-Aizik, Shlomit, additional, Schenk, Simon, additional, Snyder, Michael P., additional, Tracy, Russell P., additional, Vanderboom, Patrick, additional, Trappe, Scott, additional, Walsh, Martin J., additional, Evans, Charles R., additional, Fernandez, Facundo M., additional, Li, Yafeng, additional, Sanford, James A., additional, Tomlinson, Lyl, additional, Lee Alekel, D., additional, Bekirov, Iddil, additional, Boyce, Amanda T., additional, Boyington, Josephine, additional, Fleg, Jerome L., additional, Joseph, Lyndon J.O., additional, Laughlin, Maren R., additional, Maruvada, Padma, additional, Morris, Stephanie A., additional, McGowan, Joan A., additional, Nierras, Concepcion, additional, Pai, Vinay, additional, Peterson, Charlotte, additional, Ramos, Ed, additional, Roary, Mary C., additional, Williams, John P., additional, Xia, Ashley, additional, Cornell, Elaine, additional, Rooney, Jessica, additional, Miller, Michael E., additional, Ambrosius, Walter T., additional, Rushing, Scott, additional, Stowe, Cynthia L., additional, Jack Rejeski, W., additional, Nicklas, Barbara J., additional, Pahor, Marco, additional, Lu, Ching-ju, additional, Trappe, Todd, additional, Chambers, Toby, additional, Raue, Ulrika, additional, Lester, Bridget, additional, Bergman, Bryan C., additional, Bessesen, David H., additional, Jankowski, Catherine M., additional, Kohrt, Wendy M., additional, Melanson, Edward L., additional, Moreau, Kerrie L., additional, Schauer, Irene E., additional, Schwartz, Robert S., additional, Kraus, William E., additional, Slentz, Cris A., additional, Huffman, Kim M., additional, Johnson, Johanna L., additional, Willis, Leslie H., additional, Kelly, Leslie, additional, Houmard, Joseph A., additional, Dubis, Gabriel, additional, Broskey, Nick, additional, Goodpaster, Bret H., additional, Sparks, Lauren M., additional, Coen, Paul M., additional, Cooper, Dan M., additional, Haddad, Fadia, additional, Rankinen, Tuomo, additional, Ravussin, Eric, additional, Johannsen, Neil, additional, Harris, Melissa, additional, Jakicic, John M., additional, Newman, Anne B., additional, Forman, Daniel D., additional, Kershaw, Erin, additional, Rogers, Renee J., additional, Nindl, Bradley C., additional, Page, Lindsay C., additional, Stefanovic-Racic, Maja, additional, Barr, Susan L., additional, Rasmussen, Blake B., additional, Moro, Tatiana, additional, Paddon-Jones, Doug, additional, Volpi, Elena, additional, Spratt, Heidi, additional, Musi, Nicolas, additional, Espinoza, Sara, additional, Patel, Darpan, additional, Serra, Monica, additional, Gelfond, Jonathan, additional, Burns, Aisling, additional, Bamman, Marcas M., additional, Buford, Thomas W., additional, Cutter, Gary R., additional, Bodine, Sue C., additional, Esser, Karyn, additional, Farrar, Rodger P., additional, Goodyear, Laurie J., additional, Hirshman, Michael F., additional, Albertson, Brent G., additional, Qian, Wei-Jun, additional, Piehowski, Paul, additional, Gritsenko, Marina A., additional, Monore, Matthew E., additional, Petyuk, Vladislav A., additional, McDermott, Jason E., additional, Hansen, Joshua N., additional, Hutchison, Chelsea, additional, Moore, Samuel, additional, Gaul, David A., additional, Clish, Clary B., additional, Avila-Pacheco, Julian, additional, Dennis, Courtney, additional, Kellis, Manolis, additional, Carr, Steve, additional, Jean-Beltran, Pierre M., additional, Keshishian, Hasmik, additional, Mani, D.R., additional, Clauser, Karl, additional, Krug, Karsten, additional, Mundorff, Charlie, additional, Pearce, Cadence, additional, Ivanova, Anna A., additional, Ortlund, Eric A., additional, Maner-Smith, Kristal, additional, Uppal, Karan, additional, Zhang, Tiantian, additional, Sealfon, Stuart C., additional, Zaslavsky, Elena, additional, Nair, Venugopalan, additional, Li, SiDe, additional, Jain, Nimisha, additional, Ge, YongChao, additional, Sun, Yifei, additional, Nudelman, German, additional, Ruf-zamojski, Frederique, additional, Smith, Gregory, additional, Pincas, Nhanna, additional, Rubenstein, Aliza, additional, Anne Amper, Mary, additional, Seenarine, Nitish, additional, Lappalainen, Tuuli, additional, Lanza, Ian R., additional, Sreekumaran Nair, K., additional, Klaus, Katherine, additional, Montgomery, Stephen B., additional, Smith, Kevin S., additional, Gay, Nicole R., additional, Zhao, Bingqing, additional, Hung, Chia-Jiu, additional, Zebarjadi, Navid, additional, Balliu, Brunilda, additional, Fresard, Laure, additional, Burant, Charles F., additional, Li, Jun Z., additional, Kachman, Maureen, additional, Soni, Tanu, additional, Raskind, Alexander B., additional, Gerszten, Robert, additional, Robbins, Jeremy, additional, Ilkayeva, Olga, additional, Muehlbauer, Michael J., additional, Newgard, Christopher B., additional, Ashley, Euan A., additional, Wheeler, Matthew T., additional, Jimenez-Morales, David, additional, Raja, Archana, additional, Dalton, Karen P., additional, Zhen, Jimmy, additional, Suk Kim, Young, additional, Christle, Jeffrey W., additional, Marwaha, Shruti, additional, Chin, Elizabeth T., additional, Hershman, Steven G., additional, Hastie, Trevor, additional, Tibshirani, Robert, additional, and Rivas, Manuel A., additional

Published
2020
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15. The GTEx Consortium atlas of genetic regulatory effects across human tissues

Author

Aguet, François, Barbeira, Alvaro N, Bonazzola, Rodrigo, Brown, Andrew, Castel, Stephane E, Jo, Brian, Kasela, Silva, Kim-Hellmuth, Sarah, Liang, Yanyu, Oliva, Meritxell, Parsana, Princy E, Flynn, Elise, Fresard, Laure, Gaamzon, Eric R, Hamel, Andrew R, He, Yuan, Hormozdiari, Farhad, Mohammadi, Pejman, Muñoz-Aguirre, Manuel, Park, YoSon, Saha, Ashis, Segrć, Ayellet V, Strober, Benjamin J, Wen, Xiaoquan, Wucher, Valentin, Das, Sayantan, Garrido-Martín, Diego, Gay, Nicole R, Handsaker, Robert E, Hoffman, Paul J, Kashin, Seva, Kwong, Alan, Li, Xiao, MacArthur, Daniel, Rouhana, John M, Stephens, Matthew, Todres, Ellen, Viñuela, Ana, Wang, Gao, Zou, Yuxin, Brown, Christopher D, Cox, Nancy, Dermitzakis, Emmanouil, Engelhardt, Barbara E, Getz, Gad, Guigo, Roderic, Montgomery, Stephen B, Stranger, Barbara E, Im, Hae Kyung, Battle, Alexis, Ardlie, Kristin G, Lappalainen, Tuuli, and Universitat Politècnica de Catalunya. Doctorat en Estadística i Investigació Operativa

Subjects
Enginyeria química::Biotecnologia [Àrees temàtiques de la UPC], 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Genotype-Tissue Expression, Atlas (topology), Genetics, Computational biology, Biology, Genètica, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

The Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues, and to link these regulatory mechanisms to trait and disease associations. Here, we present analyses of the v8 data, based on 17,382 RNA-sequencing samples from 54 tissues of 948 post-mortem donors. We comprehensively characterize genetic associations for gene expression and splicing incisandtrans, showing that regulatory associations are found for almost all genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue-specificity of genetic effects, and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.

Published
2019

16. Impact of admixture and ancestry on eQTL analysis and GWAS colocalization in GTEx.

Author

Gay, Nicole R., Gloudemans, Michael, Antonio, Margaret L., Abell, Nathan S., Balliu, Brunilda, Park, YoSon, Martin, Alicia R., Musharoff, Shaila, Rao, Abhiram S., Aguet, François, Barbeira, Alvaro N., Bonazzola, Rodrigo, Hormozdiari, Farhad, Ardlie, Kristin G., Brown, Christopher D., Im, Hae Kyung, Lappalainen, Tuuli, Wen, Xiaoquan, and Montgomery, Stephen B.

Published
2020
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18. Multi-omic identification of key transcriptional regulatory programs during endurance exercise training.

Author

Smith GR, Zhao B, Lindholm ME, Raja A, Viggars M, Pincas H, Gay NR, Sun Y, Ge Y, Nair VD, Sanford JA, Amper MAS, Vasoya M, Smith KS, Montgomery S, Zaslavsky E, Bodine SC, Esser KA, Walsh MJ, and Snyder MP

Abstract

Transcription factors (TFs) play a key role in regulating gene expression and responses to stimuli. We conducted an integrated analysis of chromatin accessibility, DNA methylation, and RNA expression across eight rat tissues following endurance exercise training (EET) to map epigenomic changes to transcriptional changes and determine key TFs involved. We uncovered tissue-specific changes and TF motif enrichment across all omic layers, differentially accessible regions (DARs), differentially methylated regions (DMRs), and differentially expressed genes (DEGs). We discovered distinct routes of EET-induced regulation through either epigenomic alterations providing better access for TFs to affect target genes, or via changes in TF expression or activity enabling target gene response. We identified TF motifs enriched among correlated epigenomic and transcriptomic alterations, DEGs correlated with exercise-related phenotypic changes, and EET-induced activity changes of TFs enriched for DEGs among their gene targets. This analysis elucidates the unique transcriptional regulatory mechanisms mediating diverse organ effects of EET., Competing Interests: S.C.B. has equity in Emmyon, Inc and receives grant funding from Calico Life Sciences. M.P.S. is a cofounder and scientific advisor of Personalis, Qbio, January AI, Filtricine, SensOmics, Protos, Fodsel, Rthm, Marble and scientific advisor of Genapsys, Swaz, Jupiter. S.B.M. is a consultant for BioMarin, MyOme and Tenaya Therapeutics.

Published
2023
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19. Sexual dimorphism and the multi-omic response to exercise training in rat subcutaneous white adipose tissue.

Author

Many GM, Sanford JA, Sagendorf TJ, Hou Z, Nigro P, Whytock K, Amar D, Caputo T, Gay NR, Gaul DA, Hirshman M, Jimenez-Morales D, Lindholm ME, Muehlbauer MJ, Vamvini M, Bergman B, Fern Ndez FM, Goodyear LJ, Ortlund EA, Sparks LM, Xia A, Adkins JN, Bodine SC, Newgard CB, and Schenk S

Abstract

Subcutaneous white adipose tissue (scWAT) is a dynamic storage and secretory organ that regulates systemic homeostasis, yet the impact of endurance exercise training and sex on its molecular landscape has not been fully established. Utilizing an integrative multi-omics approach with data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we identified profound sexual dimorphism in the dynamic response of rat scWAT to endurance exercise training. Despite similar cardiorespiratory improvements, only male rats reduced whole-body adiposity, scWAT adipocyte size, and total scWAT triglyceride abundance with training. Multi-omic analyses of adipose tissue integrated with phenotypic measures identified sex-specific training responses including enrichment of mTOR signaling in females, while males displayed enhanced mitochondrial ribosome biogenesis and oxidative metabolism. Overall, this study reinforces our understanding that sex impacts scWAT biology and provides a rich resource to interrogate responses of scWAT to endurance training.

Published
2023
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20. The mitochondrial multi-omic response to exercise training across tissues.

Author

Amar D, Gay NR, Jimenez-Morales D, Beltran PMJ, Ramaker ME, Raja AN, Zhao B, Sun Y, Marwaha S, Gaul D, Hershman SG, Xia A, Lanza I, Fernandez FM, Montgomery SB, Hevener AL, Ashley EA, Walsh MJ, Sparks LM, Burant CF, Rector RS, Thyfault J, Wheeler MT, Goodpaster BH, Coen PM, Schenk S, Bodine SC, and Lindholm ME

Abstract

Mitochondria are adaptable organelles with diverse cellular functions critical to whole-body metabolic homeostasis. While chronic endurance exercise training is known to alter mitochondrial activity, these adaptations have not yet been systematically characterized. Here, the Molecular Transducers of Physical Activity Consortium (MoTrPAC) mapped the longitudinal, multi-omic changes in mitochondrial analytes across 19 tissues in male and female rats endurance trained for 1, 2, 4 or 8 weeks. Training elicited substantial changes in the adrenal gland, brown adipose, colon, heart and skeletal muscle, while we detected mild responses in the brain, lung, small intestine and testes. The colon response was characterized by non-linear dynamics that resulted in upregulation of mitochondrial function that was more prominent in females. Brown adipose and adrenal tissues were characterized by substantial downregulation of mitochondrial pathways. Training induced a previously unrecognized robust upregulation of mitochondrial protein abundance and acetylation in the liver, and a concomitant shift in lipid metabolism. The striated muscles demonstrated a highly coordinated response to increase oxidative capacity, with the majority of changes occurring in protein abundance and post-translational modifications. We identified exercise upregulated networks that are downregulated in human type 2 diabetes and liver cirrhosis. In both cases HSD17B10, a central dehydrogenase in multiple metabolic pathways and mitochondrial tRNA maturation, was the main hub. In summary, we provide a multi-omic, cross-tissue atlas of the mitochondrial response to training and identify candidates for prevention of disease-associated mitochondrial dysfunction.

Published
2023
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