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Cell Journal، جلد ۱۷، شماره Suppl ۱، صفحات ۲۰-۲۰
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عنوان انگلیسی Os-3: Epigenetic Mechanisms in Neural Stem Cells; Implicating The Role of DNA Methylation and MeCP2
چکیده انگلیسی مقاله Multipotent neural stem cells (NSC) self-renew and differentiate into different cell types of the central nervous system. The process of NSC differentiation is tightly controlled by epigenetic mechanisms that dictate NSC fate commitments. An important epigenetic modification with key roles in brain development and NSC differentiation is methylation of DNA molecules. Two most studied types of DNA methylation are 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). My lab studies the role of 5mC and 5hmC in NSC differentiation and their impact in neurological disorders. Our studies are mainly focused on MeCP2, which is the main 5mC- and 5hmC-binding protein in brain. MeCP2 is a highly abundant epigenetic factor in brain and its loss-of-function mutations cause Rett Syndrome, a severe from of autism spectrum disorders. Currently, Rett Syndrome has no cure and the pathobiology of the disease is not fully understood. Our initial studies in MeCP2-deficient mouse were proof-of-principle for the role of MeCP2 isoforms in differentiated adult NSC. We reported the first generation of preclinical MeCP2 gene therapy vectors and performed high efficient gene therapy delivery into NSC, neurons and brain microenvironment. Since 2009, my lab has devoted an intensive focus on the transcriptional control and functional role of MeCP2 isoforms and MeCP2 genetic-epigenetic regulatory networks in neural stem cells. This knowledge is critical to establish outcome measures in identifying possible therapy strategies for Rett Syndrome. To this end, we recently identified an FDA approved drug (Decitabine) that induces MeCP2 expression in neural stem cells via altered DNA methylation at the cis regulatory elements. In differentiating NSC, we showed that Decitabine globally alters 5mC and 5hmC levels. In a side-by-side comparison of Decitabine and selected chemical compounds(proposed for Rett Syndrome therapeutic applications), we studied their impact in activating MeCP2 regulatory network and promoting NSC neurogenesis. Our data are not only important for therapeutic applications of Rett Syndrome, but also for other MeCP2-associated neurological conditions, such as autism, and X-linked mental disability, that currently have no cure.
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نویسندگان مقاله m رستگار | m rastegar


نشانی اینترنتی http://celljournal.org/journal/article/abstract/56
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