Early adverse exposures, such as maternal stress during pregnancy and child abuse, are thought to result in long-lasting consequences on neural circuit function and stress hormone regulation and ultimately in an increased risk for psychiatric but also medical disorders later in life. Overall, this presentation will describe putative molecular mechanisms how genetic variants and exposure to adversity interact to shape risk and resilience for psychiatric disorders, with a focus on stress hormones. These glucocorticoids (GCs) have been shown to alter gene expression pattern and to induce long-lasting epigenetic changes in specific loci through binding of the glucocorticoid receptor (GR) to glucocorticoid responsive elements (GREs).
The talk will first highlight data from a human hippocampal cell line that identify long lasting epigenetic changes in DNA methylation in response to GCs. These lasting epigenetic changes are located in brain development- and disease-relevant gene enhancer regions and lead to increased transcriptional sensitivity to future stress exposure. Data from human brain organoids and single cell sequencing will then delineate whether specific subtypes of cells show differential sensitivity to early GC exposure during brain development. The second focus will be on common genetic variants in long-range enhancer elements that can modulate the transcriptional and epigenetic response to GR activation and early life adversity. These functional genetic variants associate with increased risk for psychiatric phenotypes and differences in neural correlated of stress processing and are in turn enriched among the loci showing lasting DNA methylation changes with GC in the hippocampal cell line described above.
Overall, the presentation will outline how stress-exposure can have lasting effects on cell and tissue function and how this relates to risk or resilience to stress-related disorders in the context of common genetic variation.
1. Understand how stress can lead to lasting epigenetic changes
2. Understand possible molecular mechanisms of gene x stress interactions