Epigenetics and the regulation of stress vulnerability and resilience

Abstract

The human brain has a remarkable capacity to adapt to and learn from a wide range of variations in the environment. However, environmental challenges can also precipitate psychiatric disorders in susceptible individuals. Why any given experience should induce one brain to adapt while another is edged toward psychopathology remains poorly understood. Like all aspects of psychological function, both nature (genetics) and nurture (life experience) sculpt the brain's response to stressful stimuli. Here we review how these two influences intersect at the epigenetic regulation of neuronal gene transcription, and we discuss how the regulation of genomic DNA methylation near key stress-response genes may influence psychological susceptibility or resilience to environmental stressors. Our goal is to offer a perspective on the epigenetics of stress responses that works to bridge the gap between the study of this molecular process in animal models and its potential usefulness for understanding stress vulnerabilities in humans.

Keywords: DNA methylation; epigenetics; neural plasticity; psychological stress; resilience; vulnerability.

Figure 1

Molecular mechanisms of stressor-induced regulation and their effects on stress responses. Cytosine methylation is mediated by members of the DNA methyl transferase (DNMT) family (“writers”), whereas demethylation is facilitated by proteins including Gadd45b and the Tet family (“erasers”). Proteins like MeCP2 that bind methylated cytosines and recruit transcriptional coactivators are the “readers” of this mark. The boxes show DNA methylation relevant changes that occur following specific stress paradigms. Red boxes represent epigenetic modifications associated with stress vulnerability, whereas green boxes represent modifications associated with stress resilience. To the right of the boxes are transcriptional consequences of these chromatin regulatory events. The lack of known transcriptional consequences is shown with question marks. White circles, unmethylated cytosines, black circles, methylated cytosines. Circled P represents a stimulus-regulated phosphorylation site on MeCP2. NAc, nucleus accumbens, PVN, paraventricular nucleus of the hypothalamus, LHb, lateral habenula.

Figure 2

Schematic representation of epigenetic regulation of the hypothalamic-pituitary-adrenal (HPA) axis. The left side of the figure depicts the epigenetic modifications thought to confer vulnerability and the right side the ones thought to confer resilience. Stimulatory loops between sites of the axis are shown in blue, whereas inhibitory loops are shown in red. Potential directions for future research are suggested with question marks. GR, glucocorticoid receptor; HIP, hippocampus; PVN, paraventricular nucleus.