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MeCP2-E1 isoform is a dynamically expressed, weakly DNA-bound protein with different protein and DNA interactions compared to MeCP2-E2

Alexia Martínez de Paz 1, 2 Leila Khajavi 3, 4, 5 Hélène Martin 4, 5 Rafael Claveria-Gimeno 6 Susanne Tom Dieck 7 Manjinder Cheema 1 Jose Sanchez-Mut 8 Malgorzata Moksa 9 Annaick Carles 9 Nick Brodie 1 Taimoor Sheikh 10 Melissa Freeman 1 Evgeniy Petrotchenko 1 Christoph Borchers 1, 11 Erin Schuman 7 Matthias Zytnicki 3 Adrian Velazquez-Campoy 6 Olga Abian 6, 12 Martin Hirst 8, 9, 13 Manel Esteller 14 John Vincent 10, 1 Cécile Malnou 4, 5 Juan Ausió 1, *
* Corresponding author
1 UVIC - University of Victoria [Canada]
2 Cornell University
3 MIAT INRA - Unité de Mathématiques et Informatique Appliquées de Toulouse
4 UT3 - Université Toulouse III - Paul Sabatier
5 INSERM U563 - CNRS UMR1037 - Centre de Physiopathologie de Toulouse-Purpan
6 University of Zaragoza - Universidad de Zaragoza [Zaragoza]
7 Max Planck Institute for Brain Research
8 EPFL - Ecole Polytechnique Fédérale de Lausanne
9 UBC - University of British Columbia
10 University of Toronto
11 Jewish General Hospital
12 I3A - Aragón Institute of Engineering Research [Zaragoza]
13 BCCRC - BC Cancer Agency
14 IDIBELL - Institut d'Investigació Biomèdica de Bellvitge [Barcelone]
Abstract : Background: MeCP2-a chromatin-binding protein associated with Rett syndrome-has two main isoforms, MeCP2-E1 and MeCP2-E2, differing in a few N-terminal amino acid residues. Previous studies have shown brain region-specific expression of these isoforms which, in addition to their different cellular localization and differential expression during brain development, suggest that they may also have non-overlapping molecular mechanisms. However, differential functions of MeCP2-E1 and E2 remain largely unexplored. Results: Here, we show that the N-terminal domains (NTD) of MeCP2-E1 and E2 modulate the ability of the methyl-binding domain (MBD) to interact with DNA as well as influencing the turn-over rates, binding dynamics, response to neuronal depolarization, and circadian oscillations of the two isoforms. Our proteomics data indicate that both isoforms exhibit unique interacting protein partners. Moreover, genome-wide analysis using ChIP-seq provide evidence for a shared as well as a specific regulation of different sets of genes. Conclusions: Our study supports the idea that Rett syndrome might arise from simultaneous impairment of cellular processes involving non-overlapping functions of MECP2 isoforms. For instance, MeCP2-E1 mutations might impact stimuli-dependent chromatin regulation, while MeCP2-E2 mutations could result in aberrant ribosomal expression. Overall, our findings provide insight into the functional complexity of MeCP2 by dissecting differential aspects of its two isoforms.
Keywords : MeCP2 Isoforms Chromatin Rett syndrome
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Journal articles
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https://hal.inrae.fr/hal-03114362
Contributor : Papa Abdoulaye Sow <>
Submitted on : Monday, January 18, 2021 - 8:30:15 PM
Last modification on : Monday, January 25, 2021 - 11:42:48 AM

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Alexia Martínez de Paz, Leila Khajavi, Hélène Martin, Rafael Claveria-Gimeno, Susanne Tom Dieck, et al.. MeCP2-E1 isoform is a dynamically expressed, weakly DNA-bound protein with different protein and DNA interactions compared to MeCP2-E2. Epigenetics & Chromatin, BioMed Central, 2019, 12 (1), ⟨10.1186/s13072-019-0298-1⟩. ⟨hal-03114362⟩

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