Sex Differences in the Epigenome: A Cause or Consequence of Sexual Differentiation of the Brain?

Abstract

Females and males display differences in neural activity patterns, behavioral responses, and incidence of psychiatric and neurological diseases. Sex differences in the brain appear throughout the animal kingdom and are largely a consequence of the physiological requirements necessary for the distinct roles of the two sexes in reproduction. As with the rest of the body, gonadal steroid hormones act to specify and regulate many of these differences. It is thought that transient hormonal signaling during brain development gives rise to persistent sex differences in gene expression via an epigenetic mechanism, leading to divergent neurodevelopmental trajectories that may underlie sex differences in disease susceptibility. However, few genes with a persistent sex difference in expression have been identified, and only a handful of studies have employed genome-wide approaches to assess sex differences in epigenomic modifications. To date, there are no confirmed examples of gene regulatory elements that direct sex differences in gene expression in the brain. Here, we review foundational studies in this field, describe transcriptional mechanisms that could act downstream of hormone receptors in the brain, and suggest future approaches for identification and validation of sex-typical gene programs. We propose that sexual differentiation of the brain involves self-perpetuating transcriptional states that canalize sex-specific development.

Keywords: epigenetics; estrogen; gene regulation; neurodevelopment; sex differences.

Figure 1

Developmental landscapes of brain cell fate specification. In Waddington’s description of the epigenetic landscape [6,7], the ball rolling down the hill represents the developmental trajectory of an embryo: The landscape itself is pre-specified by the genetic makeup of the organism, but the chosen path can be altered by extrinsic events. As development progresses, the valley slopes steepen, representing the inevitable canalization of a genetic program as cells differentiate and their plasticity is restricted. Near birth, the rodent brain is bipotential and can easily progress to a female or male fate. A) The brain, like the gonads, develops by default as female. B) In males, testosterone is converted to estradiol in the brain and activates a gene expression program that irreversibly pushes the brain towards a male fate. In both sexes, puberty is an additional sensitive period when sexually differentiated circuitry is acted on by sex-specific hormonal profiles.

Figure 2

Proposed positive feedback mechanism responsible for maintaining sex-specific cell fates. ERα: estrogen receptor alpha; TF: transcription factor.