MeCP2 gene dosage-dependent neurodevelopmentally restricted defects arise by aberrant activation of cell fate-determining bivalent genes.

The overexpression of MECP2 leads to severe neurological deficits in MECP2 duplication syndrome, and its dosage is considered a risk factor in gene therapy for Rett syndrome. However, in MECP2 duplication syndrome patients, MECP2 dysregulation arises at the embryonic stage while in Rett syndrome gene therapy, MECP2 is delivered into the mature brain. Here, we show that MeCP2 overexpression induces transcriptional alterations in neural progenitor cells, but has minimal effects in neurons in both mouse and human contexts. Consequently, MeCP2 overexpression in neural progenitor cells, but not mature neurons, leads to functional changes. Mechanistically, we observe that both endogenous and overexpressed Mecp2 bind to the same CpG island repertoire. In neurons, where endogenous Mecp2 is highly expressed, ectopic protein expression leads to reduced CpG island binding and accelerated protein degradation. In contrast, in neural progenitor cells, lower endogenous Mecp2 levels facilitate stronger deposition of the ectopic protein onto CpG islands, driving the transcriptional activation of many developmental bivalent genes. We show that this activation is mediated by the interaction with the SWI/SNF chromatin remodeling complex. Our findings establish that increased gene dosage-dependent effects are highly influenced by cell type, levels of proteins and their mechanisms of action.