Glucocorticoid Exposure During Hippocampal Neurogenesis Primes Future Stress Response by Inducing Long-Lasting Changes in DNA Methylation [methylation]

ABSTRACT: Prenatal stress exposure is associated with the risk for psychiatric disorders later in life. This may be mediated via enhanced exposure to glucocorticoids (GCs), known to impact neurogenesis. We aimed to identify molecular mediators of these effects, focusing on long-lasting epigenetic changes. In a human hippocampal progenitor cell (HPC) line, we assessed the short- and long-term effects of GC exposure during neurogenesis on mRNA expression and DNA methylation (DNAm) profiles. GC exposure induced changes in DNAm at 27,812 CpG sites and in the expression of 3,857 transcripts at FDR ≤ 0.1 and an absolsute change in expression of 1.15. HPC gene expression and GC-affected DNAm profiles were enriched for changes observed during human fetal brain development. Differentially methylated sites (DMSs) with GC exposure clustered into four trajectories over HPC-differentiation, with transient as well as long-lasting DNAm changes. Lasting DMSs mapped to distinct functional pathways and were selectively enriched for poised and bivalent enhancer marks. Lasting DMSs had little correlation with lasting gene expression changes, but were associated with a significantly enhanced transcriptional response to a second acute GC challenge. A significant subset of lasting DMSs was also responsive to an acute GC-challenge in peripheral blood. These tissue-overlapping DMSs were used to compute a poly-epigenetic score that predicted exposure to conditions of excessive prenatal GC in newborn cord blood. Overall, our data suggest that early exposure to GCs can change the set point of future transcriptional responses to stress by inducing lasting DNAm changes. Such altered set points may relate to differential vulnerability to stress exposure later in life.

ORGANISM(S): Homo sapiens

PROVIDER: GSE119846 | GEO | 2019/03/01

REPOSITORIES: GEO