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Background  Aberrant MeCP2 expression in brain is associated with neurodevelopmental disorders including autism. In the brain of stressed mouse and autistic human patients, reduced MeCP2 expression is correlated with  Mecp2 / MECP2  promoter hypermethylation. Altered expression of MeCP2 isoforms (MeCP2E1 and MeCP2E2) is associated with neurological disorders, highlighting the importance of proper regulation of both isoforms. While known regulatory elements (REs) within the  MECP2/Mecp2  promoter and intron 1 are involved in  MECP2/Mecp2  regulation,  Mecp2  isoform-specific regulatory mechanisms are unknown .  We hypothesized that DNA methylation at these REs may impact the expression of  Mecp2  isoforms.    Methods  We used a previously characterized  in vitro  differentiating neural stem cell (NSC) system to investigate the interplay between  Mecp2  isoform-specific expression and DNA methylation at the  Mecp2  REs. We studied altered expression of  Mecp2  isoforms, affected by global DNA demethylation and remethylation, induced by exposure and withdrawal of decitabine (5-Aza-2′-deoxycytidine). Further, we performed correlation analysis between DNA methylation at the  Mecp2  REs and the expression of  Mecp2  isoforms after decitabine exposure and withdrawal.    Results  At different stages of NSC differentiation,  Mecp2  isoforms showed reciprocal expression patterns associated with minor, but significant changes in DNA methylation at the  Mecp2  REs. Decitabine treatment induced  Mecp2e1 /MeCP2E1 (but not  Mecp2e2 ) expression at day (D) 2, associated with DNA demethylation at the  Mecp2  REs. In contrast, decitabine withdrawal downregulated both  Mecp2  isoforms to different extents at D8, without affecting DNA methylation at the  Mecp2  REs. NSC cell fate commitment was minimally affected by decitabine under tested conditions. Expression of both isoforms negatively correlated with methylation at specific regions of the  Mecp2  promoter, both at D2 and D8. The correlation between intron 1 methylation and  Mecp2e1  (but not  Mecp2e2 ) varied depending on the stage of NSC differentiation (D2: negative; D8: positive).    Conclusions  Our results show the correlation between the expression of  Mecp2  isoforms and DNA methylation in differentiating NSC, providing insights on the potential role of DNA methylation at the  Mecp2  REs in  Mecp2  isoform-specific expression. The ability of decitabine to induce  Mecp2e1 /MeCP2E1, but not  Mecp2e2  suggests differential sensitivity of  Mecp2  isoforms to decitabine and is important for future drug therapies for autism.

Decitabine alters the expression of Mecp2 isoforms via dynamic DNA methylation at the Mecp2 regulatory elements in neural stem cells