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Disruption of MeCP2–TCF20 complex underlies distinct neurodevelopmental disorders

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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8794850/
https://www.ncbi.nlm.nih.gov/pubmed/35074918
http://dx.doi.org/10.1073/pnas.2119078119
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author 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.
author_facet 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.
author_sort Zhou, Jian
collection PubMed
description 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.
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spelling pubmed-87948502022-07-24 Disruption of MeCP2–TCF20 complex underlies distinct neurodevelopmental disorders 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. Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2022-01-24 2022-01-25 /pmc/articles/PMC8794850/ /pubmed/35074918 http://dx.doi.org/10.1073/pnas.2119078119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
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.
Disruption of MeCP2–TCF20 complex underlies distinct neurodevelopmental disorders
title Disruption of MeCP2–TCF20 complex underlies distinct neurodevelopmental disorders
title_full Disruption of MeCP2–TCF20 complex underlies distinct neurodevelopmental disorders
title_fullStr Disruption of MeCP2–TCF20 complex underlies distinct neurodevelopmental disorders
title_full_unstemmed Disruption of MeCP2–TCF20 complex underlies distinct neurodevelopmental disorders
title_short Disruption of MeCP2–TCF20 complex underlies distinct neurodevelopmental disorders
title_sort disruption of mecp2–tcf20 complex underlies distinct neurodevelopmental disorders
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8794850/
https://www.ncbi.nlm.nih.gov/pubmed/35074918
http://dx.doi.org/10.1073/pnas.2119078119
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