Molecular pathogenesis of several neurodevelopmental disorders converges on MeCP2-TCF20 complex interactions

Neurodevelopmental disorders (NDDs) are genetically heterogeneous, yet often share certain features such as intellectual disability or motor incoordination. MeCP2 dysfunction is associated with MECP2 duplication syndrome and Rett syndrome (RTT), the phenotypes of which overlap with other NDDs, yet the precise molecular pathogenesis remains unclear. Using proximity-dependent biotinylation (BioID), we identified a novel TCF20 complex that interacts with MeCP2 through its subunit PHF14. TCF20 regulates the expression of key neuronal genes, many of which are co-regulated by MeCP2. Reducing Tcf20 partially rescued the behavioral deficits caused by MECP2 overexpression, underscoring a functional relationship between MeCP2 and TCF20 in NDD pathogenesis. We identified a patient with a missense mutation in PHF14 that abolishes the MeCP2-PHF14-TCF20 interaction who exhibits neurological features seen in RTT. These data demonstrate the critical role of MeCP2-TCF20 complex interaction for brain function. RNA-seq was performed on whole-cell RNA from prefrontal cortex tissue from 3 Tcf20+/- and 3 WT mice, 3 Phf14+/- and 3 WT mice, 5 MeCP2 KO and 5 WT mice.