Stress during puberty and adulthood pregnancy impact histone acetylation regulators in the hypothalamus

Undergoing stressful events during puberty puts women at risk for a variety of negative outcomes, and this risk is heightened if they become pregnant later in life. We previously demonstrated that stress during puberty combined with pregnancy in adulthood led to a blunted response of the hypothalamic-pituitary-adrenal stress axis in humans and mice. We have begun to understand the mechanisms underlying this effect by examining the paraventricular nucleus of the hypothalamus (PVN), a key regulator of the HPA axis. Prior studies uncovered an increase in chromatin openness within the PVN of the at-risk mice, with bioinformatic analyses implicating histone acetylation in this increased openness. Here, we measured the activity of histone acetyltransferase (HATs) and histone deacetylase (HDACs), the writers and erasers of histone acetylation, within the PVN to further characterize how stress during puberty and pregnancy may be interacting to produce a blunted stress response. We found that histone acetylation tone within the PVN is predictive of prior transcriptional and chromatin results. Pregnant, pubertally stressed females had a pro-acetylation tone within the PVN that was driven by decrease in HDAC activity. These findings establish a role for regulators of acetylation in the open chromatin landscape characteristic in the PVN of pregnant, pubertally stressed females. Overall, this study provides insight into the epigenetic mechanisms underlying female-relevant risk for stress dysregulation, a central endophenotype of affective disorders.