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 messenger RNA levels were higher in the amygdala 2 h after tone-shock presentations, compared with 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.

中文翻译：

---

HDAC4的雌激素依赖性与雌性小鼠和PTSD妇女的恐惧相关。

妇女在发生创伤事件后患上创伤后应激障碍（PTSD）的风险增加。最近的研究表明，这可能部分是由循环的雌激素水平介导的。这项研究评估了以下假设：对雌激素水平的个体差异会导致女性恐惧调节和PTSD风险。我们评估了Grady Trauma项目女性参与者血液中的DNA甲基化，发现血清雌二醇水平与整个基因组中的DNA甲基化相关。对于血液中表达的基因，我们使用针对细胞比例和年龄进行调整的线性模型，检查了每个CpG位点与PTSD诊断之间的关联。经过多次测试校正后，PTSD与HDAC4基因中CpG位点的甲基化有关，该基因编码组蛋白脱乙酰基酶4，并参与长期记忆的形成和行为。HDAC4 CpG位点的DNA甲基化被附近的单核苷酸多态性（rs7570903）标记，这也与受创伤的人类杏仁核的HDAC4表达，恐惧增强的惊吓和静止状态功能连接有关。在啮齿动物模型中使用听觉巴甫洛夫恐惧条件，我们检查了卵巢切除的（OVX）雌性小鼠杏仁核中Hdac4的调控。与OVX笼养对照雌性相比，音震后2小时杏仁核中Hdac4信使RNA水平更高。在自然循环的雌性动物中，相对于笼养动物的肠胃（低雌激素）组，音调震荡表现增加了Hdac4的表达，而对于前列腺（高雌激素组）则没有。一起，