Disruption of MeCP2–TCF20 complex underlies distinct neurodevelopmental disorders

Abstract

MeCP2 is associated with Rett syndrome (RTT), <i>MECP2</i> duplication syndrome, and a number of conditions with isolated features of these diseases, including autism, intellectual disability, and motor dysfunction. MeCP2 is known to broadly bind methylated DNA, but the precise molecular mechanism driving disease pathogenesis remains to be determined. Using proximity-dependent biotinylation (BioID), we identified a transcription factor 20 (TCF20) complex that interacts with MeCP2 at the chromatin interface. Importantly, RTT-causing mutations in <i>MECP2</i> disrupt this interaction. TCF20 and MeCP2 are highly coexpressed in neurons and coregulate the expression of key neuronal genes. Reducing <i>Tcf20</i> partially rescued the behavioral deficits caused by <i>MECP2</i> overexpression, demonstrating a functional relationship between MeCP2 and TCF20 in <i>MECP2</i> duplication syndrome pathogenesis. We identified a patient exhibiting RTT-like neurological features with a missense mutation in the PHF14 subunit of the TCF20 complex that abolishes the MeCP2-PHF14-TCF20 interaction. Our data demonstrate the critical role of the MeCP2-TCF20 complex for brain function.