SSA: Elucidation of epigenomic and transcriptional mechanisms controlling stress-induced Fkbp5 gene expression in the hippocampus

This PhD studentship is an exciting project to obtain insight into how stress impacts on the brain at
the molecular level. Stress is part of everybody's life. It can become a health problem when a stressful
situation is extremely traumatic, when exposure to stress becomes chronic, and in cases where there
is an underlying genetic vulnerability. Recently, a genetic vulnerability (a so-called single nucleotide
polymorphism (SNP)) for developing major depression and posttraumatic stress disorder was
described for the gene Fkbp5 (Klengel et al. Nature Neurosci. 2013). The protein product of this gene,
Fkbp51, reduces the sensitivity of the glucocorticoid receptor for binding the stress hormones cortisol
or corticosterone, glucocorticoid hormones in man and rodents, respectively. Excessive stimulation of
the glucocorticoid receptor is thought to have detrimental effects on the brain; therefore, Fkbp51
plays an important role in keeping glucocorticoid receptor activity within healthy limits. Accordingly,
to maintain health and wellbeing appropriate expression of the Fkbp5 gene is of major importance.
Presently, however there is only limited information available about how the gene is regulated.
Glucocorticoid receptors are known to stimulate expression of the Fkbp5 gene and raise cellular levels
of Fkbp51 protein, thus resulting in reduction of receptor sensitivity to respond to stress hormone.
Recently, we discovered that glucocorticoid receptors bind to so-called glucocorticoid-response
elements within the Fkbp5 gene in the hippocampus after stress in vivo (Mifsud & Reul, Proc. Natl.
Acad. Sci. USA 2016).
The aim of this project is to elucidate how the activity of the Fkbp5 gene is regulated by glucocorticoid
receptors and epigenetic factors like histone modifications and DNA methylation status in vivo. You
will apply a range of state-of-the-art molecular techniques including chromatin immuno-precipitation
(ChIP), quantitative PCR, hnRNA and mRNA analysis and DNA methylation analysis, bioinformatics
analysis, radioimmunoassays as well as animal experimentation including surgeries. To obtain deeper
insight into the functional properties of particular segments of the Fkbp5 gene in vitro you will use the
front-line gene editing Crispr/Cas9 technology.
This project will be supervised by Professor Johannes Reul and Dr Oscar Cordero Llana at the University
of Bristol and Professor Jonathan Mill at the University of Exeter.