title: Epigenetics and sex differences in the brain: A genome-wide comparison of histone-3 lysine-4 trimethylation (H3K4me3) in male and female mice.
abstract: Many neurological and psychiatric disorders exhibit gender disparities, and sex differences in the brain likely explain some of these effects. Recent work in rodents points to a role for epigenetics in the development or maintenance of neural sex differences, although genome-wide studies have so far been lacking. Here we review the existing literature on epigenetics and brain sexual differentiation and present preliminary analyses on the genome-wide distribution of histone-3 lysine-4 trimethylation in a sexually dimorphic brain region in male and female mice. H3K4me3 is a histone mark primarily organized as 'peaks' surrounding the transcription start site of active genes. We microdissected the bed nucleus of the stria terminalis and preoptic area (BNST/POA) in adult male and female mice and used ChIP-Seq to compare the distribution of H3K4me3 throughout the genome. We found 248 genes and loci with a significant sex difference in H3K4me3. Of these, the majority (71%) had larger H3K4me3 peaks in females. Comparisons with existing databases indicate that genes and loci with increased H3K4me3 in females are associated with synaptic function and with expression atlases from related brain areas. Based on RT-PCR, only a minority of genes with a sex difference in H3K4me3 has detectable sex differences in expression at baseline conditions. Together with previous findings, our data suggest that there may be sex biases in the use of epigenetic marks. Such biases could underlie sex differences in vulnerabilities to drugs or diseases that disrupt specific epigenetic processes.
authors.affiliation: Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Erica Y
authors.initials: EY
authors.lastname: Shen
authors.affiliation: Center for Behavioral Neuroscience, Department of Psychology, Quinnipiac University, Hamden, CT 06518, USA.
authors.forename: Todd H
authors.initials: TH
authors.lastname: Ahern
authors.affiliation: Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01604, USA.
authors.forename: Iris
authors.initials: I
authors.lastname: Cheung
authors.affiliation: Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01604, USA.
authors.forename: Juerg
authors.initials: J
authors.lastname: Straubhaar
authors.affiliation: Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomics Science, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Aslihan
authors.initials: A
authors.lastname: Dincer
authors.affiliation: Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01604, USA.
authors.forename: Isaac
authors.initials: I
authors.lastname: Houston
authors.affiliation: Neuroscience Institute, Georgia State University, Atlanta, GA 30302, USA.
authors.forename: Geert J
authors.initials: GJ
authors.lastname: de Vries
authors.affiliation: Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Schahram
authors.initials: S
authors.lastname: Akbarian
authors.affiliation: Neuroscience Institute, Georgia State University, Atlanta, GA 30302, USA. Electronic address: nforger@gsu.edu.
authors.forename: Nancy G
authors.initials: NG
authors.lastname: Forger
mesh_terms: D000818:Animals; D001921:Brain / Q000502:physiology*; D057890:Epigenomics; D005260:Female; D006657:Histones / Q000235:genetics*; D008239:Lysine / Q000235:genetics; D008297:Male; D051379:Mice; D012727:Sex Characteristics
chemical_list: D006657:Histones; D008239:Lysine
keywords: Bed nucleus of the stria terminalis; ChIP-Seq; Histone; Methylation; Preoptic area; Sex difference