Biotin tagging of MeCP2 reveals contextual insights into the Rett syndrome transcriptome

Mutations in MECP2 cause Rett syndrome (RTT), a X-linked neurological disorder characterized by the regressive loss of neurodevelopmental milestones and acquired intellectual disability and motor impairments. However, the cellular heterogeneity of the mammalian brain impedes our understanding of how MECP2 mutations disrupt neuronal function and contribute to RTT. In response, we developed cell type-specific biotin tagging in mice bearing RTT-associated mutations and profiled nuclear transcriptomes in WT and mutant neurons. Although individual gene expression changes are largely specific to each mutation and cell type, higher-level transcriptional features remain conserved and correlate with RTT phenotypic severity. Furthermore, subcellular RNA populations support post-transcriptional compensation as a basis for the upregulation of long genes previously reported in RTT mutant neurons. Finally, we overcame the genetic mosacism associated with female RTT mouse models and identified functionally distinct gene expression changes in neighboring WT and mutant neurons, which altogether provide key contextual insights into RTT. Overall design: Nuclear total RNA-seq of two types of neurons of male and female RTT mice and GRO-seq of the cortex