Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.
McLean Hospital, Harvard Medical School, Belmont, MA, USA.
Mol Psychiatry. 2018 Mar;23(3):658-665. doi: 10.1038/mp.2016.250. Epub 2017 Jan 17.
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.
女性在经历创伤性事件后，患创伤后应激障碍（PTSD）的风险增加。最近的研究表明，这可能部分是由循环雌激素水平介导的。本研究评估了这样一种假设，即个体对雌激素水平的反应差异有助于女性的恐惧调节和 PTSD 风险。我们评估了 Grady 创伤项目中女性参与者的血液 DNA 甲基化情况，发现血清雌二醇水平与全基因组的 DNA 甲基化有关。对于在血液中表达的基因，我们使用线性模型检查了每个 CpG 位点与 PTSD 诊断之间的关联，该模型调整了细胞比例和年龄。在多重检验校正后，PTSD 与 HDAC4 基因的 CpG 位点甲基化相关，该基因编码组蛋白去乙酰化酶 4，参与长期记忆形成和行为。HDAC4 CpG 位点的 DNA 甲基化由附近的单核苷酸多态性（rs7570903）标记，该多态性也与 HDAC4 表达、恐惧增强的惊吓和创伤后人类杏仁核的静息状态功能连接相关。在啮齿动物模型中使用听觉巴甫洛夫恐惧条件反射，我们检查了卵巢切除（OVX）雌性小鼠杏仁核中 Hdac4 的调节。与 OVX-笼内对照雌性相比，在声音-电击呈现后 2 小时，杏仁核中的 Hdac4 信使 RNA 水平更高。在自然循环的雌性中，与笼内对照相比，声音-电击呈现增加了 Hdac4 的表达，而在动情前期（雌激素低）而不是动情期（雌激素高）组中没有增加。这些结果共同支持了 HDAC4 调节和表达的雌激素影响，这可能导致女性 PTSD。
