Chronic stress-driven glucocorticoid receptor activation programs key cell phenotypes and functional epigenomic patterns in human fibroblasts

Calvin S Leung; Oksana Kosyk; Emma M Welter; Nicholas Dietrich; Trevor K Archer; Anthony S Zannas

doi:10.1016/j.isci.2022.104960

Chronic stress-driven glucocorticoid receptor activation programs key cell phenotypes and functional epigenomic patterns in human fibroblasts

iScience. 2022 Aug 17;25(9):104960. doi: 10.1016/j.isci.2022.104960. eCollection 2022 Sep 16.

Authors

Calvin S Leung¹, Oksana Kosyk¹, Emma M Welter¹, Nicholas Dietrich², Trevor K Archer², Anthony S Zannas^{1

3

4}

Affiliations

¹ Department of Psychiatry, University of North Carolina, Chapel Hill, NC 27599, USA.
² Chromatin and Gene Expression Section, Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
³ Department of Genetics, University of North Carolina, Chapel Hill, NC 27514, USA.
⁴ Carolina Stress Initiative, University of North Carolina School of Medicine, Chapel Hill, NC 27514, USA.

Abstract

Chronic environmental stress can profoundly impact cell and body function. Although the underlying mechanisms are poorly understood, epigenetics has emerged as a key link between environment and health. The genomic effects of stress are thought to be mediated by the action of glucocorticoid stress hormones, primarily cortisol in humans, which act via the glucocorticoid receptor (GR). To dissect how chronic stress-driven GR activation influences epigenetic and cell states, human fibroblasts underwent prolonged exposure to physiological stress levels of cortisol and/or a selective GR antagonist. Cortisol was found to drive robust changes in cell proliferation, migration, and morphology, which were abrogated by concomitant GR blockade. The GR-driven cell phenotypes were accompanied by widespread, yet genomic context-dependent, changes in DNA methylation and mRNA expression, including gene loci with known roles in cell proliferation and migration. These findings provide insights into how chronic stress-driven functional epigenomic patterns become established to shape key cell phenotypes.

Keywords: Biological sciences; Endocrinology; Molecular biology; Transcriptomics.