Disruption of MeCP2-TCF20 complex underlies distinct neurodevelopmental disorders

Authors: ZHOU, JIAN - Baylor College Of Medicine; HAMDAN, HAMDAN - Baylor College Of Medicine; YALAMANCHILI, HARI - Children'S Nutrition Research Center (CNRC); PANG, KAIFANG - Baylor College Of Medicine; POHODICH, AMY - Texas Children'S Hospital; LOPEZ, JOANNA - Baylor College Of Medicine; SHAO, YINGYAO - Baylor College Of Medicine; OSES-PRIETO, JUAN - University Of California San Francisco (UCSF); LI, LIFANG - Baylor College Of Medicine; KIM, WONHO - Baylor College Of Medicine; DURHAM, MARK - Texas Children'S Hospital; BAJIKAR, SAMEER - Baylor College Of Medicine; PALMER, DONNA - Baylor College Of Medicine; NG, PHILIP - Baylor College Of Medicine; THOMPSON, MICHELLE - Hudsonalpha Institute For Biotechnology; BEBIN, E - University Of Alabama At Birmingham; MULLER, AMELIE - University Of Tubingen; KUECHLER, ALMA - Essen University Hospital; KAMPMEIER, ANTJE - Essen University Hospital; HAAK, TOBIAS - University Of Tubingen; BURLINGAME, ALMA - University Of California San Francisco (UCSF); LIU, ZHANDONG - Texas Children'S Hospital; RASBAND, MATTHEW - Baylor College Of Medicine; ZOGHBI, HUDA - Baylor College Of Medicine

Submitted to: Proceedings of the National Academy of Sciences (PNAS)
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/13/2021
Publication Date: 1/24/2022
Citation: Zhou, J., Hamdan, H., Yalamanchili, H.K., Pang, K., Pohodich, A.E., Lopez, J., Shao, Y., Oses-Prieto, J.A., Li, L., Kim, W., Durham, M.A., Bajikar, S.S., Palmer, D.J., Ng, P., Thompson, M.L., Bebin, E.M., Muller, A.J., Kuechler, A., Kampmeier, A., Haak, T.B., Burlingame, A.L., Liu, Z., Rasband, M.N., Zoghbi, H.Y. 2022. Disruption of MeCP2-TCF20 complex underlies distinct neurodevelopmental disorders. Proceedings of the National Academy of Sciences (PNAS). 119(4). Article e2119078119. https://doi.org/10.1073/pnas.2119078119.
DOI: https://doi.org/10.1073/pnas.2119078119

Interpretive Summary: About 3-5% of children in the US suffer from some type of neurodevelopmental disorders. Distinct mutations in the methyl-CpG-binding protein 2 (MECP2) gene are known to result in Rett syndrome (RTT), MECP2 duplication syndrome (MDS), and other neurodevelopmental disorders, which present with overlapping symptoms like autistic behaviors, epilepsy, intellectual disability, and motor dysfunction. Although the genetic basis of these MECP2-associated disorders is known, the precise mechanism underlying disease pathogenesis has remained a mystery. While large-scale sequencing and bioinformatics approaches have led us to the genetic mutations underlying some of these conditions, in this study researchers adopt a combinatorial approach coupling protein interactions with genetic studies in disease model to understand the pathogenesis of the disease. This study discovered the TCF20 complex and its interplay with MECP2 during normal brain development as well as TCF20's role in the pathogenesis of Rett syndrome. Importantly, this study showed that reducing TCF20 levels relieved some anxiety-like and abnormal social behavior as well as learning and memory deficits seen in mice with neuro developmental disorders and lay a promising path towards potential care and therapeutic strategies.

Technical 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.