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ISDN2014_0213: Epigenetic regulation of MeCP2 in neural stem cells and adult brain: Implication of therapeutic strategies for MeCP2‐related neurodevelopmental disorders
Author(s) -
Liyanage Vichithra R.B.,
Zachariah Robby M.,
Rastegar Mojgan
Publication year - 2015
Publication title -
international journal of developmental neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.761
H-Index - 88
eISSN - 1873-474X
pISSN - 0736-5748
DOI - 10.1016/j.ijdevneu.2015.04.177
Subject(s) - medical genetics , regenerative medicine , library science , medicine , gerontology , stem cell , genetics , biology , computer science , gene
MeCP2 is a major epigenetic modulator in brain. Mutations and expression deficits of MeCP2 cause several neurodevelopmental disorders including Rett syndrome and Autism, which do not have any cure. Even though a thorough understanding of MeCP2 regulation in brain is required to design therapeutic strategies, mechanisms by which MeCP2 is regulated in brain remain elusive. Potential role of promoter DNA methylation in repressing MeCP2 expression in human autistic brains and stressed mouse brain have been shown before. Objectives: In this study, we investigated the role of DNA methylation at the Mecp2 regulatory elements (REs) within the Mecp2 promoter and intron 1 in regulating Mecp2/MeCP2 expression in vitro and in vivo. We used an established in vitro model of neurogenesis [differentiating neural stem cells (NSCs)] and adult mouse brain regions. Further, we aimed to test the ability of an FDA approved epigenetic drug to induce the Mecp2/MeCP2 expression through DNA methylation changes during neurogenesis. Methods: We studied DNA methylation by using bisulfite pyrosequencing in differentiating NSCs and seven brain regions in the adult mouse. We treated the differentiating NSC with the epigenetic drug Decitabine at the onset of NSC differentiation and studied changes in Mecp2/MeCP2 expression and DNA methylation. Results: Our results show dynamic DNA methylation profiles at the Mecp2 REs which correlated with Mecp2 expression at different stages of NSC differentiation and in the studied brain regions. The Decitabine treatment of NSCs significantly induced Mecp2/MeCP2 expression both at transcript and protein levels in association with DNA demethylation of the Mecp2 REs. Conclusions: Our studies provide evidence for the epigenetic regulation of Mecp2 expression by DNA methylation during neurogenesis and in adult brain. The ability of Decitabine to induce Mecp2/MeCP2 expression during neurogenesis provides insights on potential drug therapy to restore or induce Mecp2/MeCP2 expression in MeCP2 deficiency-related neurodevelopmental disorders.