title: 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 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.
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.|McLean Hospital, Harvard Medical School, Belmont, MA, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Maddox
authors.affiliation: Department of Psychiatry, School of Medicine, Emory University, Atlanta, GA, USA.
authors.forename: V
authors.initials: V
authors.lastname: Kilaru
authors.affiliation: Center for Advanced Brain Imaging (CABI), Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Shin
authors.affiliation: Department of Psychiatry, School of Medicine, Emory University, Atlanta, GA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Jovanovic
authors.affiliation: Department of Psychiatry, School of Medicine, Emory University, Atlanta, GA, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Almli
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.|Department of Psychiatry, School of Medicine, Emory University, Atlanta, GA, USA.
authors.forename: B G
authors.initials: BG
authors.lastname: Dias
authors.affiliation: Department of Psychiatry, School of Medicine, Emory University, Atlanta, GA, USA.|Atlanta VA Medical Center, Atlanta, GA, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Norrholm
authors.affiliation: Department of Psychiatry, School of Medicine, Emory University, Atlanta, GA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Fani
authors.affiliation: Department of Psychiatry, School of Medicine, Emory University, Atlanta, GA, USA.
authors.forename: V
authors.initials: V
authors.lastname: Michopoulos
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Ding
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA, USA.
authors.forename: K N
authors.initials: KN
authors.lastname: Conneely
authors.affiliation: Department of Psychiatry, School of Medicine, Emory University, Atlanta, GA, USA.|Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: E B
authors.initials: EB
authors.lastname: Binder
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.|McLean Hospital, Harvard Medical School, Belmont, MA, USA.|Department of Psychiatry, School of Medicine, Emory University, Atlanta, GA, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Ressler
authors.affiliation: Department of Psychiatry, School of Medicine, Emory University, Atlanta, GA, USA.|Department of Gynecology and Obstetrics, School of Medicine, Emory University, Atlanta, GA, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Smith
mesh_terms: D000328:Adult; D000679:Amygdala / Q000378:metabolism; D000818:Animals; D003214:Conditioning, Classical / Q000502:physiology; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D004958:Estradiol / Q000032:analysis / Q000097:blood; D004967:Estrogens / Q000378:metabolism / Q000502:physiology; D005239:Fear / Q000502:physiology* / Q000523:psychology; D005260:Female; D006655:Histone Deacetylases / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013216:Reflex, Startle / Q000502:physiology; D012097:Repressor Proteins / Q000378:metabolism* / Q000502:physiology; D013313:Stress Disorders, Post-Traumatic / Q000235:genetics* / Q000378:metabolism
chemical_list: D004967:Estrogens; D012097:Repressor Proteins; D004958:Estradiol; C400300:HDAC4 protein, human; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases