Maternal Separation Followed by Chronic Mild Stress in Adulthood Is Associated with Concerted Epigenetic Regulation of AP-1 Complex Genes

Depression is one of the most prevalent mental diseases worldwide. Patients with psychiatric diseases often have a history of childhood neglect, indicating that early-life experiences predispose to psychiatric diseases in adulthood. Two strong models were used in the present study: the maternal separation/early deprivation model (MS) and the chronic mild stress model (CMS). In both models, we found changes in the expression of a number of genes such as Creb and Npy. Strikingly, there was a clear regulation of expression of four genes involved in the AP-1 complex: c-Fos, c-Jun, FosB, and Jun-B. Interestingly, different expression levels were observed depending on the model, whereas the combination of the models resulted in a normal level of gene expression. The effects of MS and CMS on gene expression were associated with distinct histone methylation/acetylation patterns of all four genes. The epigenetic changes, like gene expression, were also dependent on the specific stressor or their combination. The obtained results suggest that single life events leave a mark on gene expression and the epigenetic signature of gene promoters, but a combination of different stressors at different life stages can further change gene expression through epigenetic factors, possibly causing the long-lasting adverse effects of stress.