Understanding stress-responsive molecular networks
Host: MAX-PLANCKGESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV, Germany
PhD awarding institution: LUDWIGMAXIMILIANSUNIVERSITAET MUENCHEN
Lead Supervisor: E Binder
Objectives: Exposure to stressful life events is one of the strongest risk factors for psychiatric disorders, but also contributes risk for a number of medical disorders. These stressful events are difficult to measure objectively. To nevertheless investigate how genetic variants may modify the impact of the environment a stimulated QTL approach can be adopted, in which genetic variants are identified that alter the transcriptional response to a hormonal mediator of the stress response (Arloth et al. 2015). A main mediator of the stress response is the glucocorticoid receptor (GR), a nuclear receptor with transcription factor function. Understanding the interplay of genetic and epigenetic factors that moderate an individual’s transcriptional response to GR could aid prevention of stress-related disorders and help to identify individuals at high risk for stress-related disorders. Building on our own published results on stress-moderating variants shown to associate with risk for psychiatric disorders (Arloth et al. 2015; Elbau et al. 2018), the aim of this project is to 1) integrate multi-omic datasets of GR response. LCLs of individuals carrying either high or low polygenic load of variants associated with either strong or weaker transcriptional GR response will undergo RNA-seq, DNA methyl-capture Seq, GR-ChIP Seq and HiC-Seq to understand the molecular underpinnings of how common genetic variants alter GR-response. 2) The regulatory capacity of these variants will be investigated using STARR-Seq. This approach will allow to identify mechanisms of differential cellular stress response and to refine a SNP set predictive of stress-susceptibility by identification of the functional variants. This information will be summarized in functionally informed, experimentally weighted polygenic stress score to apply to clinical cohorts.