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MeCP2 heterochromatin organization is modulated by arginine methylation and serine phosphorylation

Schmidt, Annika; Frei, Jana; Poetsch, Ansgar; Chittka, Alexandra; Zhang, Hui; Assmann, Chris; Lehmkuhl, Anne; ... Cardoso, M Cristina; + view all (2022) MeCP2 heterochromatin organization is modulated by arginine methylation and serine phosphorylation. Frontiers in Cell and Developmental Biology , 10 , Article 941493. 10.3389/fcell.2022.941493. Green open access

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Abstract

Rett syndrome is a human intellectual disability disorder that is associated with mutations in the X-linked MECP2 gene. The epigenetic reader MeCP2 binds to methylated cytosines on the DNA and regulates chromatin organization. We have shown previously that MECP2 Rett syndrome missense mutations are impaired in chromatin binding and heterochromatin reorganization. Here, we performed a proteomics analysis of post-translational modifications of MeCP2 isolated from adult mouse brain. We show that MeCP2 carries various post-translational modifications, among them phosphorylation on S80 and S421, which lead to minor changes in either heterochromatin binding kinetics or clustering. We found that MeCP2 is (di)methylated on several arginines and that this modification alters heterochromatin organization. Interestingly, we identified the Rett syndrome mutation site R106 as a dimethylation site. In addition, co-expression of protein arginine methyltransferases (PRMT)1 and PRMT6 lead to a decrease of heterochromatin clustering. Altogether, we identified and validated novel modifications of MeCP2 in the brain and show that these can modulate its ability to bind as well as reorganize heterochromatin, which may play a role in the pathology of Rett syndrome.

Type: Article
Title: MeCP2 heterochromatin organization is modulated by arginine methylation and serine phosphorylation
Location: Switzerland
Open access status: An open access version is available from UCL Discovery
DOI: 10.3389/fcell.2022.941493
Publisher version: https://doi.org/10.3389/fcell.2022.941493
Language: English
Additional information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Keywords: Science & Technology, Life Sciences & Biomedicine, Cell Biology, Developmental Biology, arginine (di)methylation, heterochromatin organization, MeCP2, protein arginine methyltransferases, Rett syndrome, RETT-SYNDROME MUTATIONS, CPG BINDING DOMAIN, METHYLTRANSFERASE PRMT6, PHASE-SEPARATION, TRANSCRIPTIONAL REPRESSION, HISTONE DEACETYLASE, DNA METHYLATION, STEM-CELLS, PROTEIN, ASSOCIATION
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
URI: https://discovery.ucl.ac.uk/id/eprint/10156945
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