Sex-biased methylome and transcriptome in human prefrontal cortex

Abstract

Brain function and cognitive performance differ between men and women in some measures. The phenotypic variation may be partially due to sex differences in epigenomes and transcriptomes in specific brain regions [e.g. the prefrontal cortex (PFC)]. Genome-wide DNA methylation and gene expression were examined in postmortem PFC of 32 males and 14 females (all were Caucasians) using Illumina's 450K Methylation and HT-12 v4 Gene Expression BeadChips, respectively. Multiple linear regression, Pearson correlation and DAVID functional annotation analyses were applied to investigate sex-biased DNA methylation and gene expression, DNA methylation-gene expression correlation and gene ontology (GO) annotations overrepresented by differentially methylated and expressed genes. A total of 22 124 CpGs showed differential methylation between males and females (2.6 × 10(-38) ≤ Pnominal ≤ 0.05), and the P-values of 8357 CpGs withstood multiple-testing correction (q < 0.05). A total of 1489 genes showed differential expression between males and females (4.1 × 10(-36) ≤ Pnominal ≤ 0.05), and the P-values of 35 genes survived multiple-testing correction (q < 0.05). A significant correlation (Pcorrelation < 0.05) was observed between methylation levels of 585 differentially methylated CpGs (Pnominal ≤ 0.05) and expression levels of 188 differentially expressed host genes (Pnominal < 0.05). The GO terms enriched by these 188 genes (134 on autosomes and 54 on sex chromosomes) were assigned to 24 clusters, and 33 genes involved in the top cluster (enrichment score: 4.7) mainly participate in ribosome structure and function, RNA binding and protein translation. This study demonstrated sex-specific methylomic and transcriptomic profiles in the human PFC. Our findings suggest that sex-biased DNA methylation and gene expression could be either the cause or consequence of differential brain development between males and females.

miRNAs Differentially Expressed by Next-Generation Sequencing in Cord Blood Buffy Coat Samples of Boys and Girls

“…For example, Tsai et al reported sex differences in histone acetylation in neonatal mouse brain [26]. Similarly, Xu et al have demonstrated sex bias in the methylome and transcriptome of the human prefrontal cortex [27]. We recently reported on sex differences in genome-wide DNA methylation in newborns [28].…”

Sex differences in DNA methylation and expression in zebrafish brain: a test of an extended ‘male sex drive’ hypothesis

“…Eckhardt et al, using 2,524 autosomal loci, could not detect any statistical differences between male and female samples from 12 different tissues [33]. Among the studies investigating human brain tissue, two showed more hypermethylated autosomal sites in females than in males [18,34], and two studies on the chromosomes was also noted in a study on mice brain [22]. Higher prevalence of sex-biased methylation sites on different chromosomes could be potentially linked to sex-specific functions of the genes on these chromosomes.…”

Epigenetic mechanisms in sexual differentiation of the brain and behaviour

“…Evidence suggests that only rarely do differences in DNA methylation at a single site relate to measureable differences in gene expression. In a recent whole-genome study of sex differences in DNA methylation in the human prefrontal cortex, for example, about 6% of the CpG sites that were differentially methylated in men and women correlated with a sex difference in transcription [53]. The odds get a little better going in the other direction: starting with a significant sex difference in gene transcription, a significant difference in DNA methylation was found about 35% of the time (but even then, only three-fourths of those were in the predicted direction) [53].…”