Epigenetically programming gender identity

Science Signaling  12 May 2015:
Vol. 8, Issue 376, pp. ec120
DOI: 10.1126/scisignal.aac5294

The presence or absence of a Y chromosome dictates our biological gender. However, the brain is wired to be female unless exposed to testicular steroids (such as androgen and its metabolite estradiol) during a sensitive period shortly before and after birth. The most sexually dimorphic region in the brain is the preoptic area (POA). Nugent et al. found that steroid-induced gender identity in the POA is mediated by an epigenetic mechanism, specifically DNA methylation. The best characterized form of DNA methylation occurs at cytosine residues that are adjacent to guanines (CpG islands). DNA methyltransferase (DNMT) activity and CpG methylation were lower in the POA of male newborn rats than in those of female newborn rats. Subcutaneously injecting newborn female rats with estradiol induced a decrease in DNMT activity and CpG methylation for a few days. DNMT activity did not differ before or after the sensitive perinatal period, with or without estradiol injections. Intracerebral injection of the DNMT inhibitors zebularin or RG108 in female newborn rats mimicked the effect of estradiol on DNMT activity and produced neuronal morphology, protein marker patterns, and adult anxiety-related and sexual behavior more typical of male mice, without affecting the estrous cycle. In addition, adult female mice that lacked Dnmt3a in the POA from birth had anxiety and sexual behaviors more typical of male mice. However, unlike estradiol exposure, the masculinizing effects of knocking out Dnmt3a were not restricted to the sensitive perinatal period, suggesting that enduring DNA methylation maintains the female phenotype in the brain. RNA sequencing of the POA from postnatal male or female rats revealed that a subset of genes derepressed by DNMT inhibition in females was associated with sexual differentiation. The findings further define how neurological gender identity is determined.

B. M. Nugent, C. L. Wright, A. C. Shetty, G. E. Hodes, K. M. Lenz, A. Mahurkar, S. J. Russo, S. E. Devine, M. M. McCarthy, Brain feminization requires active repression of masculinization via DNA methylation. Nat. Neurosci. 18, 690–697 (2015). [PubMed]