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Abstract

Early life adversity (ELA) is an important risk factor for the manifestation of various psychiatric disorders later in life. Prenatal and postnatal brain development comprises a time of heightened neuronal plasticity, and ELA during these periods can lead to long-lasting changes in the formation of neuronal activity-dependent circuitries and structures in conjunction with epigenetic marking of genes important to cognition, mood, and behavior. Among various epigenetic marks, DNA methylation is the best characterized besides histone modifications and chromatin remodeling factors. ELA during critical windows of development can cause sustained deregulation of the hypothalamic-pituitary-adrenal (HPA) axis, a major mediator of the stress response, whose deregulation during the course of major depression is thought to recall ELA exposure. ELA in mice evokes epigenetic programming of the hypothalamic neuropeptide arginine vasopressin (Avp), a critical driver of the HPA axis, with the epigenetic reader methyl-CpG-binding protein 2 (Mecp2) playing an important role in the establishment and maintenance of ELA-dependent epigenetic marks. Similarly, Mecp2 mediates epigenetic programming of pituitary pro-opiomelanocortin (Pomc), a downstream effector of the neuronal stress response. Overall, these studies suggest that Mecp2 integrates ELA at different levels of the HPA axis and point to the need for timely therapeutic interventions to prevent the progression of potentially harmful epigenetic marks.