Diverse roles of MeCP2 in the specification and maintenance of midbrain dopamine phenotype.
Midbrain dopamine (DA) neurons are associated with locomotor and psychiatric disorders. DA neuronal phenotype is specified in ancestral progenitors and maintained throughout differentiation. Here we demonstrate that premature MeCP2 expression prevents DA progenitors from acquiring DA phenotype through interfering NURR1 transactivation. By contrast, the maintenance of DA phenotype is not affected by MeCP2 overexpression in DA neurons. By analyzing the DNA methylation and MeCP2 binding to the promoter of DA phenotype gene tyrosine hydroxylase (Th) along differentiation, we show that Th expression is determined by TET1-mediated de-methylation of NURR1 binding sites within Th promoter. Premature MeCP2 dominates the DNA binding of these sites thereby blocking TET1 function in DA progenitors, whereas TET1 prevents excessive MeCP2 binding in DA neurons. Finally, we show that targeted de-methylation in DA progenitors protects phenotype specification from premature MeCP2 expression, whereas targeted methylation disturbs phenotype maintenance in MeCP2-overexpressed DA neurons. These findings demonstrate MeCP2 as a novel determining factor for DA neuronal phenotype and function.