Non-CG methylation and multiple epigenetic layers associate child abuse with immune and small GTPase dysregulation

Early-life adversity (ELA), including child abuse and other forms of early-life maltreatment, is a major predictor of negative mental health outcomes. ELA is thought to increase lifetime risk of psychopathology by epigenetically regulating genomic regions that in turn adjust different brain systems. Here, focusing on the lateral amygdala, a major brain site for emotional homeostasis, we comprehensively describe molecular cross-talk across multiple epigenetic mechanisms, including 6 histone marks, DNA methylation and the transcriptome, in subjects with a history of ELA and healthy controls. We first provide evidence for previously unknown interactions among epigenetic layers in the healthy brain. Focusing on non-CG methylation, and particularly on CAC, our results further suggest that the immune system and small GTPase signaling are the most consistently impaired pathways in the amygdala of ELA individuals. Overall, the present work provides new insight into epigenetic regulation of brain plasticity as a function of early-life experience.