Epigenetic contributions to hormonally-mediated sexual differentiation of the brain

Abstract

It has been long established that hormones exert enduring influences on the developing brain that direct the reproductive response in adulthood, although the cellular mechanisms by which organisational effects are maintained have not been determined satisfactorily. Recent interest in epigenetic modifications to the nervous system has highlighted the potential for hormone-induced changes to the genome that could endure for the lifespan but not be transmitted to the next generation. Preliminary evidence suggests that this is indeed possible because sex differences in the histone code and in the methylation of CpGs in the promoters of specific genes have been identified and, at times, functionally correlated with behaviour. The present review provides an overview of epigenetic processes and discusses the current state-of-the-art, and also identifies future directions.

Keywords: development; hypothalamus; oestrogens; preoptic area; sex differences; steroids: neuroactive steroids.

Fig. 1

The histone code. Nucleosomes are the fundamental unit of chromatin and consist of an octomer of histones of four varieties. Modifications to key amino acids in the carbon chain tails alter the electric charge which either repels or attracts the molecules and thereby gates the accessibility of transcription factors to the DNA. The dominant sites of modification are the lysines (K), which are either acetylated or methylated and sometimes both. Additional modifications include ubiquitination, as well as palmitylation and glycosylation (not shown here). Changes to the histone tail are achieved by specific enzymes, such as histone acetyl transferases and histone deactylases. The ‘histone code’ refers to the predictable effect of specific modifications on gene expression versus repression.

Fig. 2

Methylation of the DNA. Cytosines located proximal to guanines are the target of methylation by the DNA methyl transferase (DNMT) enzymes. Two classes of DNMT’s, DNMT1 and DNMT3, mediate maintenance versus de novo methylation. Increased methylation of cytosines can alter gene transcription directly by sterically hindering the access of transcription factors, or indirectly by recruiting methyl-binding domain (MBD) proteins, the most famous of which is MeCP2. Some MBDs, such as Kaiso, are also capable of binding to unmethylated DNA and recruiting DNMT activity. The relationship between cytosine methylation and gene expression is not as straightforward as that for changes to the histones.

Fig. 3

Epigenetics and sexual differentiation. Oestradiol (E₂) binds to and activates its nuclear transcription factor receptor (ER) which moves to the DNA and recruits a transcriptional complex. Included in this complex are enzymes with histone-acetylating ability to allow access to the DNA. Activated ER may also modify the activity of DNA methyl transferase (DNMT) enzymes and thereby alter the methylation status of the DNA. Taken together, these changes may provide the molecular basis for the organisational effects of early hormone exposure, which endure into adulthood and direct activational responses to sex-typic gonadal steroids. CBP, CREB-binding protein; HATs, histone acetyl transferases.