Estrogen-dependent association of HDAC4 with fear in female mice and women with PTSD

Abstract

Women are at increased risk of developing post-traumatic stress disorder (PTSD) following a traumatic event. Recent studies suggest that this may be mediated, in part, by circulating estrogen levels. This study evaluated the hypothesis that individual variation in response to estrogen levels contributes to fear regulation and PTSD risk in women. We evaluated DNA methylation from blood of female participants in the Grady Trauma Project and found that serum estradiol levels associates with DNA methylation across the genome. For genes expressed in blood, we examined the association between each CpG site and PTSD diagnosis using linear models that adjusted for cell proportions and age. After multiple test correction, PTSD associated with methylation of CpG sites in the HDAC4 gene, which encodes histone deacetylase 4, and is involved in long-term memory formation and behavior. DNA methylation of HDAC4 CpG sites were tagged by a nearby single nucleotide polymorphism (rs7570903), which also associated with HDAC4 expression, fear-potentiated startle and resting state functional connectivity of the amygdala in traumatized humans. Using auditory Pavlovian fear conditioning in a rodent model, we examined the regulation of Hdac4 in the amygdala of ovariectomized (OVX) female mice. Hdac4 mRNA levels were higher in the amygdala 2h after tone-shock presentations, compared to OVX-homecage control females. In naturally cycling females, tone-shock presentations increased Hdac4 expression relative to homecage controls for metestrous (low estrogen) but not the proestrous (high estrogen) group. Together, these results support an estrogenic influence of HDAC4 regulation and expression that may contribute to PTSD in women.

Exposure to polybrominated biphenyl (PBB) associates with genome-wide DNA methylation differences in peripheral blood

“…Complementary to estrogen related transcription factor binding sites being enriched near the PBBassociated CpGs, the effect size for CpGs associated with estradiol levels is correlated with the effect size of those CpGs with PBB, both in the total cohort (R = 0.20, p < 2.2e-16) and in the female participants (N = 381, R = 0.16, p < 2.2e-16. Figure S10) [48]. Additionally, of the 700 PBBassociated CpGs that were also in the estradiol analysis, 211 of them of them were also significantly associated with estradiol.…”

“…Because PBB is a known endocrine-disrupting compound and the participants of the Michigan PBB Registry have reported endocrine-related health problems, whether the epigenetic signal from PBB overlapped with the epigenetic signal from estradiol was tested. Enrichment of estradiol associated CpGs was tested using a chi-square test and results from a previously published epigenome-wide study [48]. Because these were identified using data from the Infinium HumanMethylation450 BeadChip, the results from this study were first subset to the probes interrogated by both studies (N = 401,387).…”

Genome‐wide DNA methylation investigation of glucocorticoid exposure within buccal samples

“…MDD, PTSD, and stressful life events have all been associated with changes in DNA methylation (DNAm) . To tease out the role of GC themselves, rodent models of GC exposure have been employed.…”

Neuroepigenetics of Post-Traumatic Stress Disorder

“…In contrast to these male-specific findings, a recent study set out to test the hypothesis that individual variation in response to estrogen levels contributes to fear regulation and PTSD risk in women 114 ; this hypothesis is especially notable given the twofold increased risk of PTSD in women compared to men 3 . Drawing again on participants from the Grady Trauma Project, and focusing on genes with demonstrated expression in blood, the investigators identified a single CpG site that associated with PTSD following Bonferroni correction, which fell within the histone deacetylase 4 ( HDAC4 ) gene: methylation was higher in PTSD cases than controls; and higher methylation at this site was associated with lower estradiol levels.…”

“…Summary of 43 human-based epigenetic studies of PTSD published as of July 2017, enumerated and categorized according to relevant biological system or Epigenome-wide association (EWAS) approach: Hypothalamic-Pituitary Adrenal (HPA) Axis 105,108,116,119,139–150 ; EWAS 91–96,151–155 ; Age-related CpGs 129,132,133 ; Serotonergic system 156,157 ; Neurotrophin 117,158 ; Dopaminergic System 159 ; Catecholaminergic system 102 ; DNA methylation machinery 160 ; Estrogen-responsive genes 114 ; Immune Function 161 ; Other 162–165 .…”