Disruption of MeCP2-TCF20 complex underlies distinct neurodevelopmental disorders

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 119; no. 4; p. 1
• Main Authors: Zhou, Jian, Hamdan, Hamdan, Yalamanchili, Hari Krishna, Pang, Kaifang, Pohodich, Amy E, Lopez, Joanna, Shao, Yingyao, Oses-Prieto, Juan A, Li, Lifang, Kim, Wonho, Durham, Mark A, Bajikar, Sameer S, Palmer, Donna J, Ng, Philip, Thompson, Michelle L, Bebin, E Martina, Müller, Amelie J, Kuechler, Alma, Kampmeier, Antje, Haack, Tobias B, Burlingame, Alma L, Liu, Zhandong, Rasband, Matthew N, Zoghbi, Huda Y
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 25.01.2022
• Subjects: Alleles; Animals; Autism; Biological Sciences; Biomarkers; Biotinylation; Brain - metabolism; Chromatin; Deoxyribonucleic acid; Disease Models, Animal; Disease Susceptibility; DNA; Gene expression; Intellectual disabilities; MeCP2 protein; Methyl-CpG binding protein; Methyl-CpG-Binding Protein 2 - genetics; Methyl-CpG-Binding Protein 2 - metabolism; Mice; Mice, Knockout; Mice, Transgenic; Missense mutation; Models, Biological; Multiprotein Complexes - metabolism; Mutation; Neurodevelopmental disorders; Neurodevelopmental Disorders - etiology; Neurodevelopmental Disorders - metabolism; Neurons - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Pathogenesis; Protein Binding; Reproduction (copying); Rett syndrome; Synapses - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; BioID; MeCP2; TCF20 complex; neurodevelopmental disorders; Rett syndrome
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2119078119

MeCP2 is associated with Rett syndrome (RTT), 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 disrupt this interaction. TCF20 and MeCP2 are highly coexpressed in neurons and coregulate the expression of key neuronal genes. Reducing partially rescued the behavioral deficits caused by overexpression, demonstrating a functional relationship between MeCP2 and TCF20 in 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.