Epigenetics of early child development

Abstract

Comprehensive clinical studies show that adverse conditions in early life can severely impact the developing brain and increase vulnerability to mood disorders later in life. During early postnatal life the brain exhibits high plasticity which allows environmental signals to alter the trajectories of rapidly developing circuits. Adversity in early life is able to shape the experience-dependent maturation of stress-regulating pathways underlying emotional functions and endocrine responses to stress, such as the hypothalamo-pituitary-adrenal (HPA) system, leading to long-lasting altered stress responsivity during adulthood. To date, the study of gene-environment interactions in the human population has been dominated by epidemiology. However, recent research in the neuroscience field is now advancing clinical studies by addressing specifically the mechanisms by which gene-environment interactions can predispose individuals toward psychopathology. To this end, appropriate animal models are being developed in which early environmental factors can be manipulated in a controlled manner. Here we will review recent studies performed with the common aim of understanding the effects of the early environment in shaping brain development and discuss the newly developing role of epigenetic mechanisms in translating early life conditions into long-lasting changes in gene expression underpinning brain functions. Particularly, we argue that epigenetic mechanisms can mediate the gene-environment dialog in early life and give rise to persistent epigenetic programming of adult physiology and dysfunction eventually resulting in disease. Understanding how early life experiences can give rise to lasting epigenetic marks conferring increased risk for mental disorders, how they are maintained and how they could be reversed, is increasingly becoming a focus of modern psychiatry and should pave new guidelines for timely therapeutic interventions.

Keywords: DNA methylation; brain; chromatin; early life; epigenetics; hypothalamo–pituitary–adrenal axis.

Figure 1

The hypothalamo–pituitary–adrenal (HPA) stress axis. The neuropeptides corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) are expressed in the parvocelluar neurons of the hypothalamic nucleus paraventricularis. The joint release of CRH and AVP into the portal blood vessels leads to potent stimulation of anterior pituitary ACTH secretion and in turn of corticosterone from the adrenal glands. The activational effects of the HPA axis are counteracted by the inhibitory effects of glucocorticoid receptors expressed in the hippocampus, hypothalamus, and anterior pituitary.

Figure 2

DNA wraps around histones to form a complex referred to as chromatin. The N-terminal tails of histones serve as sites for epigenetic marking by acetylation and methylation via chromatin remodeling enzymes (e.g., HDACs, HATs, HMTs, and HDMs). DNA methylation refers to the chemical transfer of methyl groups to CpG acceptor sites through a class of enzymes known DNA methyltransferases (DNMTs). Active marks (e.g., histone acetylation and DNA hypomethylation) characterize “open” chromatin, while repressive marks (e.g., histone methylation and DNA hypermethylation) occur at “closed” chromatin.

Figure 3

Early life experience can persistently alter expression levels of key genes through epigenetic marking which can underpin changes in behavior, neuroendocrine, and stress responsivity throughout later life. Collectively, this process is referred to as epigenetic programming. The nature of the environment throughout later life, in addition to the impact of biological processes associated with aging and genetic sex, may exacerbate the effects of programming established during early life resulting in increased vulnerability to mood disorders.

Figure 4

Experience-dependent activation of neurons in the PVN during early life inhibits MeCP2 binding to and repressing the AVP gene in stressed mice. This further favors DNA hypomethylation underpinning reduced MeCP2 occupancy at the AVP enhancer and maintaining epigenetic control of AVP expression into later life.