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Title: MeCP2-E1 isoform is a dynamically expressed, weakly DNA-bound protein with different protein and DNA interactions compared to MeCP2-E2
Author: 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
Vincent, John B.
Malnou, Cécile E.
Ausió, Juan
Keywords: Cromatina
Síndrome de Rett
Rett syndrome
Issue Date: 10-Oct-2019
Publisher: BioMed Central
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.
Note: Reproducció del document publicat a:
It is part of: Epigenetics & Chromatin, 2019, vol. 12, num. 1, p. 63
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ISSN: 1756-8935
Appears in Collections:Articles publicats en revistes (Ciències Fisiològiques)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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