@article{3c18a73b08fc4a089bcf3d9f94e264cf,
title = "Disruption of MeCP2–TCF20 complex underlies distinct neurodevelopmental disorders",
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.",
keywords = "BioID, MeCP2, neurodevelopmental disorders, Rett syndrome, TCF20 complex",
author = "Jian Zhou and Hamdan Hamdan and Yalamanchili, {Hari Krishna} and Kaifang Pang and Pohodich, {Amy E.} and Joanna Lopez and Yingyao Shao and Oses-Prieto, {Juan A.} and Lifang Li and Wonho Kim and Durham, {Mark A.} and Bajikar, {Sameer S.} and Palmer, {Donna J.} and Philip Ng and Thompson, {Michelle L.} and Bebin, {E. Martina} and M{\"u}ller, {Amelie J.} and Alma Kuechler and Antje Kampmeier and Haack, {Tobias B.} and Burlingame, {Alma L.} and Zhandong Liu and Rasband, {Matthew N.} and Zoghbi, {Huda Y.}",
note = "Funding Information: ACKNOWLEDGMENTS. We thank the families for their participation in the study and the clinical teams, particularly Jill A. Rosenfeld for her help in collecting some clinical data; Alexander Trostle and Ying-Wooi Wan for assistance in RNA-sequencing data processing; the Wellcome Trust Sanger Institute for providing the Tcf20 knockout mice; Vicky Brandt for critical review of the manuscript; and the Genetically Engineered Rodent Models Core led by Jason Heaney, which is partially supported by NIH Grant P30CA125123 at Baylor College of Medicine, for generating the Phf14 knockout mouse model. This work was supported by HHMI (H.Y.Z.), the Souki Foundation (H.Y.Z.), National Institute of Neurological Disorders and Stroke Grant 5R01NS057819 (to H.Y.Z.), National Institute of Child Health and Human Development Grant 1F32HD100048-01 (to S.S.B.), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (M.N.R. and A.L.B.), NIH Grant R01NS122073 (to M.N.R.), the US Department of Agriculture under Cooperative Agreement 58-3092-0-001 (to H.K.Y.), National Institute of General Medical Sciences Grant R01-GM120033 (to Z.L.), the Huffington Foundation (Z.L.), the Alabama Genomic Health Initiative (an Alabama-State earmarked project F170303004) through the University of Alabama in Birmingham (E.M.B. and M.L.T.), Deutsche For-schungsgemeinschaft Grants 418081722 and 433158657 (to T.B.H.), the Genomic and RNA Profiling Core at Baylor College of Medicine with funding from NIH Grant 1S10OD023469, and the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the NIH under Award P50HD103555 for use of the Neurovisualization and Neurobehavioral Core facilities. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Publisher Copyright: {\textcopyright} 2022 National Academy of Sciences. All rights reserved.",
year = "2022",
month = jan,
day = "25",
doi = "10.1073/pnas.2119078119",
language = "British English",
volume = "119",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "4",
}
