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

• Type of Material: Article
• Authors: Stephanie A. Maddox, Emory University; Varun Kilaru, Emory University; Jaemin Shin, Georgia Institute of Technology; Tanja Jovanovic, Emory University; Lynn Almli, Emory University; Brian Dias, Emory University; Seth Norrholm, Emory University; Negar Fani, Emory University; Vasiliki Michopoulos, Emory University; Ziyu Ding, Emory University; Karen Conneely, Emory University; Elisabeth Binder, Emory University; Kerry Ressler, Emory University; Alicia K Smith, Emory University
• Language: English
• Date: 2017-01-17
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 The Author(s)
• Final Published Version (URL): http://dx.doi.org/10.1038/mp.2016.250
• Title of Journal or Parent Work: Molecular Psychiatry
• ISSN: 1359-4184
• Grant/Funding Information: This work was also supported by NARSAD YI award #19233 (A.K.S.) the Howard Hughes Medical Institute (K.J.R.), the Behrens-Weise foundation (E.B.B.), and in part by ORIP/OD P51OD011132 (formerly NCRR P51RR000165) Yerkes Base Grant funds.; This research was supported by the National Institutes of Health Grants MH071537 and MH096764 (K.J.R.) and MH085806 (A.K.S.).
• Keywords: EWAS; post-traumatic stress disorder
• Research Categories: Biology, Genetics

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 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.