Duncan NRI Faculty and Staff Publications
Publication Date
1-25-2022
Journal
Proceedings of the National Academy of Sciences of the United States of America
DOI
10.1073/pnas.2119078119
PMID
35074918
PMCID
PMC8794850
PubMedCentral® Posted Date
1-24-2022
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Alleles, Animals, Biomarkers, Brain, Disease Models, Animal, Disease Susceptibility, Methyl-CpG-Binding Protein 2, Mice, Mice, Knockout, Mice, Transgenic, Models, Biological, Multiprotein Complexes, Mutation, Neurodevelopmental Disorders, Neurons, Nuclear Proteins, Protein Binding, Synapses, Transcription Factors, neurodevelopmental disorders, Rett syndrome, MeCP2, BioID, TCF20 complex
Abstract
MeCP2 is associated with Rett syndrome (RTT), MECP2 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 MECP2 disrupt this interaction. TCF20 and MeCP2 are highly coexpressed in neurons and coregulate the expression of key neuronal genes. Reducing Tcf20 partially rescued the behavioral deficits caused by MECP2 overexpression, demonstrating a functional relationship between MeCP2 and TCF20 in MECP2 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.