Disruption of MeCP2-TCF20 complex underlies distinct neurodevelopmental disorders
| العنوان: | Disruption of MeCP2-TCF20 complex underlies distinct neurodevelopmental disorders |
|---|---|
| المؤلفون: | Jian Zhou, Hamdan Hamdan, Hari Krishna Yalamanchili, Kaifang Pang, Amy E. Pohodich, Joanna Lopez, Yingyao Shao, Juan A. Oses-Prieto, Lifang Li, Wonho Kim, Mark A. Durham, Sameer S. Bajikar, Donna J. Palmer, Philip Ng, Michelle L. Thompson, E. Martina Bebin, Amelie J. Müller, Alma Kuechler, Antje Kampmeier, Tobias B. Haack, Alma L. Burlingame, Zhandong Liu, Matthew N. Rasband, Huda Y. Zoghbi |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | congenital, hereditary, and neonatal diseases and abnormalities, Methyl-CpG-Binding Protein 2, Medizin, Mice, Transgenic, Models, Biological, Mice, Rett syndrome, mental disorders, Animals, BioID, Alleles, MeCP2, Mice, Knockout, Neurons, TCF20 complex, Multidisciplinary, neurodevelopmental disorders, Brain, Nuclear Proteins, Biological Sciences, nervous system diseases, Disease Models, Animal, Multiprotein Complexes, Mutation, Synapses, Disease Susceptibility, Biomarkers, Protein Binding, Transcription Factors, Neuroscience |
| الوصف: | Significance Loss-of-function mutations in MECP2 cause the neurological disorder Rett syndrome (RTT), but the precise molecular mechanism driving pathogenesis remains unclear. Using an unbiased approach to identify proteins that interact with MeCP2, we identified the transcription factor 20 (TCF20) complex and discovered that RTT-causing mutations in MECP2 disrupt this interaction. Using biochemical, morphological, behavioral, and transcriptional studies, we examined the importance of this interaction for brain function and found that the TCF20 complex plays a direct role in MeCP2-dependent gene regulation and modifies MECP2-induced synaptic and behavioral deficits. Our data uncovered a previously unknown molecular aspect of MeCP2 function and revealed a converging molecular mechanism, whereby mutations of genes encoding several subunits in the same complex contribute to shared neurological symptoms. 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. |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::acc790c42da5a7a529acd9fb29046340Test https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&origin=inward&scp=85123905308Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....acc790c42da5a7a529acd9fb29046340 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |