Epigenetics, behaviour, and health

Abstract

: The long-term effects of behaviour and environmental exposures, particularly during childhood, on health outcomes are well documented. Particularly thought provoking is the notion that exposures to different social environments have a long-lasting impact on human physical health. However, the mechanisms mediating the effects of the environment are still unclear. In the last decade, the main focus of attention was the genome, and interindividual genetic polymorphisms were sought after as the principal basis for susceptibility to disease. However, it is becoming clear that recent dramatic increases in the incidence of certain human pathologies, such as asthma and type 2 diabetes, cannot be explained just on the basis of a genetic drift. It is therefore extremely important to unravel the molecular links between the "environmental" exposure, which is believed to be behind this emerging incidence in certain human pathologies, and the disease's molecular mechanisms. Although it is clear that most human pathologies involve long-term changes in gene function, these might be caused by mechanisms other than changes in the deoxyribonucleic acid (DNA) sequence. The genome is programmed by the epigenome, which is composed of chromatin and a covalent modification of DNA by methylation. It is postulated here that "epigenetic" mechanisms mediate the effects of behavioural and environmental exposures early in life, as well as lifelong environmental exposures and the susceptibility to disease later in life. In contrast to genetic sequence differences, epigenetic aberrations are potentially reversible, raising the hope for interventions that will be able to reverse deleterious epigenetic programming.

Figure 1

Methylation and demethylation reactions. DAM = S-adenosylmethionine; dMTase = demethylase; DNMT = DNA methyltransferase.

Figure 2

The DNA methylation pattern is sculpted during development by methylation and demethylation reactions to generate a cell type-specific pattern of methylation. Circle = CG site; CH3 methylated CG site; dark line = nascent DNA strand; grey line = parental DNA strand.

Figure 3

Chromatin structure, gene expression, and DNA methylation are tightly correlated; DNA methylation and chromatin program and control gene expression. Ac = acetylated histone tails; horizontal arrow = transcription; M = methylated DNA.

Figure 4

DNA methylation silences gene expression by two mechanisms. A, Methylation interferes with binding of a transcription factor to its recognition element. B, Methylated DNA attracts methylated DNA binding proteins such as MeCP2, which recruits histone deacetylase (HDAC), corepressor Sin3A, histone methyltransferases such as SuV39, and methyl K9 H3-histone binding protein (HP1).

Figure 5

The steady-state methylation pattern is a dynamic equilibrium between methylase and demethylase activities. Different environmental exposures trigger signaling pathways, which affect chromatin structure and, in turn, affect DNA methylation.

Figure 6

Activation of chromatin by increasing acetylation facilitates demethylation. Acetylation of histones could be increased by either recruitment of histone acetyltransferases (HAT) or pharmacologic inhibition of histone deacetylases with trichostatin A (TSA). Histone acetylation facilitates interaction of demethylases with the DNA and DNA demethylation.

Figure 7

Timeline of demethylation of hippocampal glucocorticoid receptor (1₇) in response to maternal care.

Figure 8

In the adult (day 90) rat, hippocampal glucocorticoid receptor methylation of low licking/grooming and arched-back nursing (LG-ABN) offspring is reversed by trichostatin A and hypomethylation of the high LG-ABN offspring is reversed by methionine.

Figure 9

Behavioural gene programming. Maternal care elicits a signaling pathway in hippocampal neurons, leading to epigenetic reprogramming of the glucocorticoid receptor exon 1₇ promoter.

Figure 10

The implications of a lifelong dynamic epigenome. Environmental exposures impact our epigenome, which, in turn, impacts our response to these exposures. The final outcome is a change in phenotype, including effects on health status.