Abstract

Early-life stress (ELS) can lead to enduring changes in the structure and function of neural circuits and endocrine pathways, resulting in altered vulnerability thresholds for stress-related disorders such as depression and anxiety. The question addressed in this work was whether epigenetic mechanisms contribute to the long-term programming of altered hypothalamus-pituitary-adrenal axis activity in ELS (maternal separated on postnatal days 1-10) mice. Adrenocorticotropic hormone (ACTH), a key pituitary mediator of the adrenocortical response to stress, is encoded by the proopiomelanocortin (Pomc) gene. Corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) are the main upstream neural regulators of Pomc gene expression and the post-translational processing of its peptidergic products, whereas glucocorticoids, secreted by the adrenals in response to stress, exert negative feedback actions on Pomc synthesis and ACTH secretion. It was shown that Pomc mRNA level is persistently increased in ELS mice and leads to sustained hypersecretion of glucocorticoids. Interestingly, ELS causes a reduction in DNA methylation at a critical regulatory region of the Pomc gene; this occurs with some delay after onset of the stress and persists for up to 1 year. A series of experiments (including reporter-, EMSA-, IHC- and ChIP-assays) supported the concept that the adverse early-life event induces changes in Pomc gene methylation and results in persistently upregulated expression of the Pomc gene. Interestingly, stress-induced changes in DNA-methylation were found to be more pronounced in males than in females, raising the possibility that epigenetic encoding occurs in a sex-specific manner; this may help to explain sex differences in susceptibility to stress-related disorders. Collectively, the results of this study indicate that epigenetic mechanisms can serve to translate environmental cues into stable changes (“cellular memory”) in gene expression in post-mitotic tissues, without the need for alterations in the genetic code.