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

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 l...

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Detalhes bibliográficos
Autores: Martínez de Paz, Alexia, Khajavi, Leila, Martin, Hélène, Clavería Gimeno, Rafael, Dieck, Susanne Tom, Cheema, Manjinder, Sanchez-Mut, Jose Vicente, Moksa, Malgorzata M., Carles, Annaick, Brodie, Nick I., Sheikh, Taimoor I., Freeman, Melissa E., Petrotchenko, Evgeniy V., Borchers, Christoph H., Schuman, Erin M., Zytnicki, Matthias, Velazquez-Campoy, Adrian, Abian, Olga, Hirst, Martin, Esteller, Manel, 1968-, Vincent, John B., Malnou, Cécile E., Ausió, Juan
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/155228
Acesso em linha:https://hdl.handle.net/2445/155228
Access Level:acceso abierto
Palavra-chave:Cromatina
Síndrome de Rett
ADN
Chromatin
Rett syndrome
DNA
Descrição
Resumo: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.

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