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

Jessica Tollkuhn,Bruno Gegenhuber

doi:10.3390/genes10060432

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.

Highlights

Females and males display differences in neural activity patterns, behavioral responses, and incidence of psychiatric and neurological diseases
We suggest that rather than focusing on the epigenomic signature that is a consequence of cell fate decisions, researchers should identify the regulatory mechanisms of transcription factors that establish and/or maintain this signature, as this is crucial for understanding the origin of sex differences in gene expression
There are other factors that contribute to sex differences in the brain, here we focus on ERα, as this receptor is the master regulator of sexual differentiation of the rodent brain, and its role in gene regulation has been extensively studied [17]

Summary

Introduction

“In the study of development we are interested in the final state to which the system arrives, and in the course by which it gets there” C.H. (republished as Reference [4]), ten years prior to the Hershey-Chase experiments [5], he had no concept of the physical nature of a gene or what we call the “epigenome”. Rather, he intended to symbolize a developmental process through an “epigenetic landscape” [6], in which each valley represents the segregation of “developmental competence”, or the cell fate decisions made throughout embryogenesis. In Waddington’s landscape, “equilibrium is not centered on a static state, but rather on a direction or pathway of change” [7] This concept is represented by the term “homeorhesis” (rhesis meaning flow) to distinguish it from the more widely-used “homeostasis”. We suggest that rather than focusing on the epigenomic signature that is a consequence of cell fate decisions, researchers should identify the regulatory mechanisms of transcription factors that establish and/or maintain this signature, as this is crucial for understanding the origin of sex differences in gene expression

Hormone Signaling at Birth Defines Sex Differences in Brain Function

Regulation of Gene Expression in the Brain

DNA Methylation

Histone Modifications

Genome Organization

Sexual Differentiation of the Brain is Developmental Programming