Social status alters chromatin accessibility and the gene regulatory response to glucocorticoid stimulation in rhesus macaques
| Autor: | Jordan N. Kohn, Jenny Tung, Tawni Voyles, Mark E. Wilson, Luis B. Barreiro, Roger Pique-Regi, Joaquín Sanz, Noah Snyder-Mackler |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Primates Epigenomics Social Sciences Biology 03 medical and health sciences Glucocorticoid receptor 0302 clinical medicine dominance rank Receptors Glucocorticoid Commentaries Gene expression Animals Epigenetics Transcription factor Gene Glucocorticoids 030304 developmental biology Regulation of gene expression Genetics 0303 health sciences Multidisciplinary Binding Sites Fossils Biological Sciences Chromatin Assembly and Disassembly Macaca mulatta Chromatin social status 030104 developmental biology PNAS Plus Gene Expression Regulation chromatin accessibility Anthropology Psychological and Cognitive Sciences Leukocytes Mononuclear Female gene regulation 030217 neurology & neurosurgery Social status Transcription Factors |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 |
| Popis: | Significance Chronic, low social status-induced stress predicts disease susceptibility, but the molecular basis for this relationship is not well understood. We manipulated social status in female rhesus macaques to investigate how status differences alter the gene expression and chromatin accessibility response to glucocorticoids (hormones involved in stress regulation). We found that social status changes immune cell gene expression and chromatin accessibility, that glucocorticoid treatment attenuates these effects, and that the DNA of low-status animals may be less accessible to glucocorticoid response-associated transcription factors. Our results thus show that social status affects multiple aspects of immune cell gene regulation, including the 3D structure of DNA. Further, they emphasize the importance of the cellular environment in determining the strength of this relationship. Low social status is an important predictor of disease susceptibility and mortality risk in humans and other social mammals. These effects are thought to stem in part from dysregulation of the glucocorticoid (GC)-mediated stress response. However, the molecular mechanisms that connect low social status and GC dysregulation to downstream health outcomes remain elusive. Here, we used an in vitro GC challenge to investigate the consequences of experimentally manipulated social status (i.e., dominance rank) for immune cell gene regulation in female rhesus macaques, using paired control and GC-treated peripheral blood mononuclear cell samples. We show that social status not only influences immune cell gene expression but also chromatin accessibility at hundreds of regions in the genome. Social status effects on gene expression were less pronounced following GC treatment than under control conditions. In contrast, social status effects on chromatin accessibility were stable across conditions, resulting in an attenuated relationship between social status, chromatin accessibility, and gene expression after GC exposure. Regions that were more accessible in high-status animals and regions that become more accessible following GC treatment were enriched for a highly concordant set of transcription factor binding motifs, including motifs for the GC receptor cofactor AP-1. Together, our findings support the hypothesis that social status alters the dynamics of GC-mediated gene regulation and identify chromatin accessibility as a mechanism involved in social stress-driven GC resistance. More broadly, they emphasize the context-dependent nature of social status effects on gene regulation and implicate epigenetic remodeling of chromatin accessibility as a contributing factor. |
| Databáze: | OpenAIRE |
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