Elsevier

Hormones and Behavior

Volume 118, February 2020, 104680
Hormones and Behavior

Review article
Hormone-epigenome interactions in behavioural regulation

https://doi.org/10.1016/j.yhbeh.2020.104680Get rights and content

Highlights

  • Epigenetic and hormonal factors regulate transcription.

  • Hormones interact with enzymes that regulate epigenetic modifications.

  • Hormones influence behaviour by altering the epigenome.

  • Epigenetic factors regulate hormone sensitivity by modifying steroid hormone receptor expression.

  • Hormones interact with epigenetic factors to regulate sexual differentiation and behaviour.

Abstract

Interactions between hormones and epigenetic factors are key regulators of behaviour, but the mechanisms that underlie their effects are complex. Epigenetic factors can modify sensitivity to hormones by altering hormone receptor expression, and hormones can regulate epigenetic factors by recruiting epigenetic regulators to DNA. The bidirectional nature of this relationship is becoming increasingly evident and suggests that the ability of hormones to regulate certain forms of behaviour may depend on their ability to induce changes in the epigenome. Moreover, sex differences have been reported for several epigenetic modifications, and epigenetic factors are thought to regulate sexual differentiation of behaviour, although specific mechanisms remain to be understood. Indeed, hormone-epigenome interactions are highly complex and involve both canonical and non-canonical regulatory pathways that may permit for highly specific gene regulation to promote variable forms of behavioural adaptation.

Introduction

The term “epigenetics” was originally coined by Conrad Hal Waddington to describe environmental influences on gene regulation that allow for the emergence of diverse phenotypes from a single genome and as such, it emphasized the factors that regulate gene expression to guide cell fate during development (Waddington, 1942). The term subsequently evolved to describe the heritable nature of gene expression across cell division that occurs without alterations in the underlying gene sequence (Wu and Morris, 2001), thereby shifting the emphasis of epigenetics on mitotic inheritance (Deans and Maggert, 2015). Although this definition is especially useful for developmental research, the emphasis on heritability is at odds with the study of epigenetic mechanisms in non-dividing cells, such as neurons. This incompatibility has led to the use of the term neuro-epigenetics to describe the operation of molecular epigenetic mechanisms (i.e. chromatin modifications and DNA methylation; described in detail below) to regulate stimulus and experience-induced changes in gene expression in the brain (Sweatt et al., 2013). The focus on the operation of epigenetic molecular mechanisms that work “above” the genome reflects the dynamic and stable epigenetic events observed in the brain and as such, our usage of the term reflects this definition. Moreover, this usage of the term offers a framework for understanding ongoing transient and stable modifications in gene expression across the lifespan despite the stagnant nature of the genome (Powledge, 2011).

A role of epigenetic mechanisms in shaping behavioural outcomes was first elucidated in pioneering studies from Michael Meaney's lab, which showed that early life experiences program adult outcomes by altering epigenetic regulation of steroid hormone receptors (Weaver et al., 2004a; Champagne et al., 2006; rev in Champagne, 2008). This discovery implicated epigenetics as a mechanism that links experience with stable changes in gene regulation, thereby providing insight into individual differences in adult phenotypes that occur independently of genetic variation. Since that initial discovery, it has become evident that hormonal and epigenetic mechanisms interact in highly complex ways, many of which are only beginning to be understood. As such, our intent is to synthesize the main themes that emerged over the last 15 years by using specific research examples, and we refer the reader to the many excellent reviews of hormone-epigenome interactions for exhaustive coverage of the literature (Bartlett et al., 2019; Forger, 2016; Frick et al., 2015; Gray et al., 2017; McCarthy and Nugent, 2015; Stolzenberg and Champagne, 2016; Turecki and Meaney, 2016). Although interactions between hormones and epigenetic factors are not limited to steroids, we chose to focus specifically on steroid hormones, particularly glucocorticoids, because of the breadth of research on their roles in behaviour. However, many of the mechanistic principles we describe here have also been linked with other nuclear hormones, such as the thyroid hormone (Hernandez and Stohn, 2018; Li et al., 2002; Liu et al., 2006; Martinez et al., 2018; Tabachnik et al., 2017).

Section snippets

Epigenetic and hormonal factors regulate transcription

Stimulus-induced changes in gene expression are vital for establishing long-lasting behavioural modifications (McClung and Nestler, 2008) and as such, understanding factors that regulate transcription is critical for understanding behaviour. Nuclear hormone receptors regulate transcription by acting as ligand-activated transcription factors (Sever and Glass, 2013), whereas epigenetic modifications regulate sensitivity to transcription factors by changing chromatin structure and altering the

Hormones interact with epigenetic regulatory enzymes

Epigenetic changes are regulated by various enzymes that write (i.e. establish) epigenetic marks, readers that recognize the mark, and erasers that remove the marks from chromatin. The best studied epigenetic writers are histone acetyltransferases (HAT), which acetylate histones to promote transcription, and histone methyltransferases (HMT), which have diverse effects on transcription (Bannister and Kouzarides, 2011). DNA methyltransferases (DNMT) are writer enzymes that mediate de novo DNA

Epigenetic factors regulate steroid hormone receptor expression

Studies on the stable effects of maternal behaviour on offspring showed that steroid hormone expression is stably altered by epigenetic factors laid down during critical developmental windows. Specifically, variable exposure to tactile stimulation in the first 7 days of life altered DNA methylation of the ER and GR promoters in the rodent brain, thus shaping maternal behaviour and stress sensitivity in adulthood (Champagne et al., 2001; Pan et al., 2014; Pena et al., 2013; Weaver et al., 2004b

Hormones regulate epigenetic modifications to influence behaviour

It is well established that epigenetic factors regulate the expression of steroid receptors and enzymes that control the biosynthesis of steroids (rev in Martinez-Arguelles and Papadopoulos, 2010), but emerging evidence shows that hormones can also rapidly induce epigenetic changes to regulate behaviour. For example, estradiol treatment during learning alters several epigenetic factors in the hippocampus, causing increased histone acetylation, reduced HDAC2 expression, and increased DNMT3B

Interactions between epigenetics and hormones in sex differences

The observation that sex hormones regulate epigenetic marks indicates that male and female brains may have unique epigenetic profiles. Sex differences in the brain have been reported for various epigenetic marks (Auger and Auger, 2013; Kigar and Auger, 2013; Matsuda, 2014; McCarthy and Nugent, 2015; Nugent et al., 2011; Shen et al., 2015), but how these changes are established is less clear. The developmental surge of estradiol during brain masculinization is an important driver of altered ER

Implications and future directions

It is becoming clear that hormones and epigenetic factors represent two dynamic systems whose interactions depend on multiple factors, including sex, task, testing conditions, and developmental history. In addition, the relationship between hormones and epigenetics is bidirectional and occurs at multiple levels, thereby complicating the study of underlying mechanisms. In addition to the classical actions of hormone receptors as DNA-binding transcription factors, hormones can also influence the

Acknowledgements

This work was supported by NSERC Discovery Grant, NSERC Discovery Accelerator Supplement, and CIHR PJT-156414 to IBZ. The authors do not report any conflicting interests.

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