Social status alters chromatin accessibility and the gene regulatory response to glucocorticoid stimulation in rhesus macaques

• Authors: Noah Snyder-Mackler, Duke University; Joaquin Sanz, University of Montreal; Jordan N. Kohn, Emory University; Tawni Voyles, Duke University; Roger Pique-Regi, Wayne State University; Mark Wilson, Emory University; Luis B. Barreiro, CHU Sainte-Justine Research Center; Jenny Tung, Duke University
• Journal Title: Proceedings of the National Academy of Sciences
• Volume: Volume 116, Number 4
• Publisher: National Academy of Sciences | 2019-01-22, Pages 1219-1228
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1073/pnas.1811758115
• Subjects: Anthropology, Medical and Forensic; Biology, Genetics; Psychology, Behavioral
• Keywords: chromatin accessibility; dominance rank; epigenomics; gene regulation; social status; Animals; Binding Sites; Chromatin; Chromatin Assembly and Disassembly; Epigenomics; Female; Gene Expression Regulation; Glucocorticoids; Leukocytes, Mononuclear; Macaca mulatta; Receptors, Glucocorticoid; Transcription Factors

Abstract

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.