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High-throughput screening of glucocorticoid-induced enhancer activity reveals mechanisms of stress-related psychiatric disorders.

ABSTRACT: Exposure to stressful life events increases the risk for psychiatric disorders. Mechanistic insight into the genetic factors moderating the impact of stress can increase our understanding of disease processes. Here, we test 3,662 single nucleotide polymorphisms (SNPs) from preselected expression quantitative trait loci in massively parallel reporter assays to identify genetic variants that modulate the activity of regulatory elements sensitive to glucocorticoids, important mediators of the stress response. Of the tested SNP sequences, 547 were located in glucocorticoid-responsive regulatory elements of which 233 showed allele-dependent activity. Transcripts regulated by these functional variants were enriched for those differentially expressed in psychiatric disorders in the postmortem brain. Phenome-wide Mendelian randomization analysis in 4,439 phenotypes revealed potentially causal associations specifically in neurobehavioral traits, including major depression and other psychiatric disorders. Finally, a functional gene score derived from these variants was significantly associated with differences in the physiological stress response, suggesting that these variants may alter disease risk by moderating the individual set point of the stress response.

SUBMITTER: Penner-Goeke S

PROVIDER: S-EPMC10710077 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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High-throughput screening of glucocorticoid-induced enhancer activity reveals mechanisms of stress-related psychiatric disorders.

Penner-Goeke Signe S Bothe Melissa M Rek Nils N Kreitmaier Peter P Pöhlchen Dorothee D Kühnel Anne A Glaser Laura V LV Kaya Ezgi E Krontira Anthi C AC Röh Simone S Czamara Darina D Ködel Maik M Monteserin-Garcia Jose J Diener Laura L Wölfel Barbara B Sauer Susann S Rummel Christine C Riesenberg Stephan S Arloth-Knauer Janine J Ziller Michael M Labeur Marta M Meijsing Sebastiaan S Binder Elisabeth B EB

Proceedings of the National Academy of Sciences of the United States of America 20231127 49

Exposure to stressful life events increases the risk for psychiatric disorders. Mechanistic insight into the genetic factors moderating the impact of stress can increase our understanding of disease processes. Here, we test 3,662 single nucleotide polymorphisms (SNPs) from preselected expression quantitative trait loci in massively parallel reporter assays to identify genetic variants that modulate the activity of regulatory elements sensitive to glucocorticoids, important mediators of the stres ...[more]

PMID: 38011552

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Project description:Lifestyle changes involving high caloric diet, sedentary life, and/or persistent stress appear to play a role in the onset of metabolic syndrome (MetS), which is characterized by hyperglycemia, hyperinsulinemia, dyslipidemia, obesity, and type-2 diabetes. MetS in the long run appears to have cerebrovascular consequences, resulting in neuropsychiatric disorders. However, there is a paucity of molecular studies using relevant animal models of metabolic disorder-induced neuropsychiatric disorders. Here, we tried to model the clinical conditions of MetS by feeding C57bl/6 Ncrl mice a high fructose diet (Hfr) for almost 12 months. Random glucose, fasting glucose, glucose tolerance, and triglycerides did not differ significantly between the Hfr diet and Control diet (Cont) groups even after a year on the Hfr diet, except for the accelerated aging-like phenotype in coat color and shiny texture. However, exposure to chronic stress for a week induced metabolic disorder as reflected in high post-prandial blood glucose in the Hfr group, and subsequently mood disorder (depression and anxiety) (p<0.01) and cognitive disorder (p<0.01) as indicated by the behavioral tests. To uncover the underlying molecular mechanisms in the prefrontal cortex, a transcriptomic study was performed. The data analysis revealed hundreds of differentially expressed genes (DEGs) between the groups (i.e., HfrUST vs CoUST = 348 genes; CoST vs CoUST = 496 genes; HfrST vs HfrUST =226 genes and HfrST vs CoST= 18 genes). The pattern of gene expression was strikingly different in the HfrST group compared to the Ctrl group, thus correlating the phenotype, i.e. MetS induced mood and cognitive disorders. Pathway analysis of the DEGs indicated perturbations in cellular metabolism, inflammation, innate immunity, neurogenesis, vasculogenesis, ion channels, and neuronal signaling. In addition, altered epigenetic regulators appear to mediate the stress-induced precipitation of metabolic and neuropsychiatric disorders. The outcome of our study supports the hypothesis of disease susceptibility due to lifestyle changes involving a high-calorie diet and chronic stress.

Dataset Information

High-throughput screening of glucocorticoid-induced enhancer activity reveals mechanisms of stress-related psychiatric disorders.

Publications

High-throughput screening of glucocorticoid-induced enhancer activity reveals mechanisms of stress-related psychiatric disorders.

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