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)

1 UVIC - University of Victoria [Canada]
2 Cornell University [New York]
3 MIAT INRAE - 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 = Bellvitge Biomedical Research Institute

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.

Mots clés: MeCP2; Isoforms; Chromatin; Rett syndrome

Domaines: Sciences du Vivant [q-bio]

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, 2019, 12 (1), pp.1-16. ⟨10.1186/s13072-019-0298-1⟩. ⟨hal-03114362⟩