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 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.

Epigenetic mechanisms in sexual differentiation of the brain and behaviour

“…75%) had greater H3K4me3 in females, and this was seen whether the sex chromosomes or autosomes were considered ( figure 5). Also, as in [50], sex differences in H3K4me3 did not map closely onto gene expression [52]. Genes with greater H3K4me3 in females were significantly associated with synapse structure and function; the expression of such genes is presumably tightly regulated in both sexes, but males and females may do it differently.…”

“…The distribution of genes with differential H3K4me3 in the BNST/ POA of adult mice showed a sex bias; most of the genes had more of this histone mark in females than in males (red and pink shading). This was true for both autosomal and X-chromosome genes [52]. (Online version in colour.…”

“…20% or fewer differences between males and females for individual genes) [36,50,52,67]. One reason for this is almost certainly the reliance on brain homogenates, which contain a multitude of cell types.…”

Genetic and epigenetic factors underlying sex differences in the regulation of gene expression in the brain

“…Chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) has been used in different cell types of primate brain (human and non-human) to examine the genome-wide distribution of H3K4me3 (Cheung et al 2010). However, surprisingly there are very few studies exploring sex-specific regulation of mono-, di and tri-methyl H3K4 (H3K4me1/H3K4me2/H3K4me3) marks on a genome-wide scale (Shen et al 2015). This is particularly intriguing, given that several studies have reported subtle sex-dependent differences in the expression of H3K4- demethylase and methyltransferase enzymes for various brain regions.…”

Cross-generational THC exposure alters the developmental sensitivity of ventral and dorsal striatal gene expression in male and female offspring

“…Secondly, the use of marijuana by women could possibly impact not only their immediate health, but also the health of their offspring, and such potential long-term consequences are still not known. It is clear that the biological differences between males and females influence the development of neuropsychiatric phenotypes (Figueira and Ouakinin, 2010; Savic and Engel, 2014; Shen et al, 2015), but the ways in which marijuana use causes long-term problems that affect the two sexes remain largely unexplored. As such, the inclusion of females in studies of cannabis is essential to decipher the neurobiological systems vulnerable in the different sexes to also ultimately guide targeted treatments in a sex-specific manner.…”