Abstract
Mutations in the X-linked gene MECP2, the founding member of a family of proteins recognizing and binding to methylated DNA, are the genetic cause of a devastating neurodevelopmental disorder in humans, called Rett syndrome. Available evidence suggests that MECP2 protein has a critical role in activity-dependent neuronal plasticity and transcription during brain development. Moreover, recent studies in mice show that various posttranslational modifications, notably phosphorylation, regulate Mecp2’s functions in learning and memory, drug addiction, depression-like behavior, and the response to antidepressant treatment. The hypothalamic-pituitary-adrenal (HPA) axis drives the stress response and its deregulation increases the risk for a variety of mental disorders. Early-life stress (ELS) typically results in sustained HPA-axis deregulation and is a major risk factor for stress related diseases, in particular major depression. Interestingly, Mecp2 protein has been shown to contribute to ELS-dependent epigenetic programming of Crh, Avp, and Pomc, all of these genes enhance HPA-axis activity. Hereby ELS regulates Mecp2 phosphorylation, DNA binding, and transcriptional activities in a tissue-specific and temporospatial manner. Overall, these findings suggest MECP2 proteins are so far underestimated and have a more dynamic role in the mediation of the gene-environment dialog and epigenetic programming of the neuroendocrine stress system in health and disease.
Highlights
The field of epigenetics has developed from different research lines that continue to shape our current understanding
Methylation and posttranslational modifications of core histones serve to lay down epigenetic states at the level of the genetic blueprint and will be briefly touched on in this review, whereas nucleosome positioning, and non-coding RNAs among others [3] are proposed to facilitate the formation of epigenetic states
Different forms of MECP2 mutations have been identified as the genetic cause of a severe neurodevelopmental disorder in humans, named Rett syndrome [5]. These findings show that accurate interpretation of epigenetic states by regulatory factors is an important determinant for mental health and underscore the role of DNA methylation in inheritable disorders [6]
Summary
The field of epigenetics has developed from different research lines that continue to shape our current understanding. While Waddington considered virtually all aspects of gene activity during development by which a phenotype arises, Riggs and colleagues refrained from defining any kind of mechanism involved This situation has rapidly changed over the last decades due to major conceptual advancements in understanding the role of epigenetic mechanisms. Different forms of MECP2 mutations have been identified as the genetic cause of a severe neurodevelopmental disorder in humans, named Rett syndrome [5]. These findings show that accurate interpretation of epigenetic states by regulatory factors is an important determinant for mental health and underscore the role of DNA methylation in inheritable disorders [6]. We propose for MECP2 a more dynamic role by linking experience-related diseases to epigenetic bookmarking and mental disease in human
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