Leung Calvin S, Kosyk Oksana, Welter Emma M, Dietrich Nicholas, Archer Trevor K, Zannas Anthony S
Department of Psychiatry, University of North Carolina, Chapel Hill, NC 27599, USA.
Chromatin and Gene Expression Section, Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
iScience. 2022 Aug 17;25(9):104960. doi: 10.1016/j.isci.2022.104960. eCollection 2022 Sep 16.
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.
慢性环境应激会对细胞和身体功能产生深远影响。尽管其潜在机制尚不清楚，但表观遗传学已成为环境与健康之间的关键联系。应激对基因组的影响被认为是由糖皮质激素应激激素的作用介导的，在人类中主要是皮质醇，它通过糖皮质激素受体（GR）发挥作用。为了剖析慢性应激驱动的GR激活如何影响表观遗传和细胞状态，人类成纤维细胞长时间暴露于生理应激水平的皮质醇和/或选择性GR拮抗剂。研究发现，皮质醇会导致细胞增殖、迁移和形态发生显著变化，而同时使用GR阻滞剂可消除这些变化。GR驱动的细胞表型伴随着DNA甲基化和mRNA表达的广泛但依赖基因组背景的变化，包括在细胞增殖和迁移中具有已知作用的基因座。这些发现为慢性应激驱动的功能性表观基因组模式如何形成关键细胞表型提供了见解。
