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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 Martínez de Paz, Alexia; Khajavi, Leila; Martin, Hélène; Claveria-Gimeno, Rafael; Tom Dieck, Susanne; Cheema, Manjinder S.; Sanchez-Mut, Jose V.; 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
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.
Item Metadata
| Title |
MeCP2-E1 isoform is a dynamically expressed, weakly DNA-bound protein with different protein and DNA interactions compared to MeCP2-E2
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| Creator |
Martínez de Paz, Alexia; Khajavi, Leila; Martin, Hélène; Claveria-Gimeno, Rafael; Tom Dieck, Susanne; Cheema, Manjinder S.; Sanchez-Mut, Jose V.; 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
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| Contributor | |
| Publisher |
BioMed Central
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| Date Issued |
2019-10-10
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| Description |
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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| Subject | |
| Genre | |
| Type | |
| Language |
eng
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| Date Available |
2019-10-10
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| Provider |
Vancouver : University of British Columbia Library
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| Rights |
Attribution 4.0 International (CC BY 4.0)
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| DOI |
10.14288/1.0383351
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| URI | |
| Affiliation | |
| Citation |
Epigenetics & Chromatin. 2019 Oct 10;12(1):63
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| Publisher DOI |
10.1186/s13072-019-0298-1
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| Peer Review Status |
Reviewed
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| Scholarly Level |
Faculty
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| Copyright Holder |
The Author(s)
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| Rights URI | |
| Aggregated Source Repository |
DSpace
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Rights
Attribution 4.0 International (CC BY 4.0)