Epigenetic signaling in psychiatric disorders: stress and depression

Figures & data

Figure 1. Epigenetic dysregulation in the HPA axis and reward circuitry is implicated in psychiatric disorders. A majority of research on altered epigenetic regulation in depression and other stress-related disorders has focused on changes within the HPA axis (A) and the brain's reward circuitry (B), depicted here in the rodent brain. Studies examining the effects of early-life manipulations on epigenetic regulation of behavior have focused on changes within the HPA axis, in contrast to adult studies, which have concentrated on epigenetic alterations in the reward circuitry. A) Main components of the HPA axis: CRF and AVP from the paraventricular nucleus of the PVN stimulates ACTH release from the anterior pituitary, which induces glucocorticoid (cortisol [human] or corticosterone [rodent]) release from the adrenal cortex. GRs in the HPC and other brain regions mediate negative feedback to reduce the stress response. B) Depicted are the major components of the limbic-reward circuitry: dopaminergic neurons (green) project from the VTA to the NAc, PFC, AMY, and HPC, among other regions. The NAc receives excitatory glutamatergic innervation (red) from the HPC, PFC, and AMY. ACTH, adrenocorticotropic hormone; AMY, amygdala; AVP, vasopressin; CRF, corticotropin releasing factor; GRs, glucocorticoid receptors; HPA, hypothalamic-pituitary-adrenal axis; HPC, hippocampus; PFC, prefrontal cortex; PVN, hypothalamus; VTA, ventral tegmental area.

Figure 2. Chromatin structure and histone modifications at N-terminal histone tails. (A) The eukaryotic genome is organized by wrapping DNA around histone octamers to form the basic units of chromatin and nucleosomes, which are then further organized and compacted into higher ordered structures. (B) The histone octamer consists of two copies each of H2A, H2B, H3, and H4. In addition to globular domains, they each have N-terminal tails that protrude from the nucleosome, while H2A also has a C-terminal tail that displays similar regulatory features. These tails can be post-translationally modified, and all known mammalian acetylation and methylation modifications on lysine residues on each tail are highlighted. The molecules are drawn roughly to proportion to the size of the protein, although the number of residues shown is not meant to reflect the exact size of the N-terminal tails. Adapted from ref 105: Sun H, Kennedy PJ, Nestler EJ. Epigenetics of the depressed brain: role of histone acetylation and methylation. Neuropsychopharmacology. 2013;38:124-137. © 2013, American College of Neuropsychopharmacology

Table I. Effect of stress on histone post-translational modifications and gene expression. Stress at different ages alters histone modifications within different brain regions, as well as proteins and enzymes responsible for these marks. General: global changes in total cellular levels of these marks. Green indicates increases associated with stress and blue indicates decreases with stress.

Table II. Effect of stress on DNA methylation and gene expression. Stress at different ages alters DNA methylation at specific genes within different brain regions, as well as proteins and enzymes related to DNa methylation. Green indicates increases associated with stress and blue indicates decreases with stress.