Epigenetic Underpinnings of Developmental Sex Differences in the Brain

Abstract

Sexual differentiation of the brain is a crucial developmental process that enables the lifelong expression of sexually dimorphic behaviors, including those necessary for successful reproduction. During a perinatal sensitive period, gonadal hormones defeminize and masculinize the male brain, and a lack of gonadal steroids allows for feminization in the female. This hormonally-induced differentiation permanently alters neural structures, creating highly dimorphic brain regions; however, the mechanism by which hormones exert their long-lasting effects are still largely unknown. Epigenetic processes such as DNA methylation and histone modifications serve as an interface for environmental stimuli to exert control over the genome. These modifications have the capacity to activate or repress gene expression, thereby shaping the developmental outcomes of cells, circuits, and structures in the brain. Sex differences in methylation, methyl-binding proteins, and chromatin modifications indicate that epigenetic mechanism may be important for sexual differentiation of the brain. The data outlined in this review provide evidence that gonadal hormones in the neonatal brain influence epigenetic processes such as DNA methylation and histone acetylation, but also emphasize the primitive status of our current understanding of epigenetics and sexual differentiation and the brain.

Reversible DNA methylation regulates seasonal photoperiodic time measurement

“…In the adult brain, testosterone secretion maintains methylation of CpG sites in the promoter regions of steroid-responsive genes (22) (e.g., vasopressin, estrogen receptor α), and during early development, gonadal steroids exert enduring effects on CNS sexual differentiation, in part, via epigenetic modifications (23,(39)(40)(41); however, whether such changes are plastic or reversible in adulthood remains unknown. Here, we demonstrate that DNMT expression and downstream dio3 promoter methylation respond to the duration of elevated circulating MEL in a manner that mirrors reproductive responses to MEL.…”

“…DNA methylation consists of the addition of a methyl group at CpG dinucleotide residues in the mammalian DNA template (18); high levels of DNA methylation near promoter regions inhibit transcription (19). Methylation is an important epigenetic mechanism in the control of behavior and physiology (20)(21)(22)(23), because it affords rapid (24) reversible (25) and cyclical (26) regulation of gene expression. DNA methyltransferases (DNMTs) that mediate DNA methylation are catalyzed either de novo (DNMT3a and DNMT3b) or maintain methylation of DNA hemimethylated sites (DNMT1) (19).…”

Description of children with 45,X/46,XY karyotype

“…The gonads might have predominance of 45,X cell line with decreased virilization, while brain may have predominance of 46,XY cell line. Brain karyotype determines genetic gender [1,12] and is established at the time of conception. Predominance of 46,XY cell line in the brain of a child with gonads having predominance of 45,X cell line and decreased virilization will still result in male genetic brain gender.…”

Sex Steroids in Insects and the Role of the Endosymbiont Wolbachia:A New Perspective

“…The mechanisms exerted by sex hormones are strictly linked to the epigenetic machinery. For example, gonadal hormones are able to induce sex differences in DNA methylation, methyl-binding proteins and chromatin modifications necessary for a correct sexual differentiation of the brain (Nugent & McCarthy, 2011). The role for steroids in modulating epigenetic changes is attracting the growing interest of many researchers.…”