MeCP2-E1 isoform is a dynamically expressed, weakly DNA-bound protein with different protein and DNA interactions compared to MeCP2-E2
Date
2019
Authors
Martínez de Paz, Alexia
Khajavi, Leila
Martin, Hélène
Claveria‑Gimeno, Rafael
Dieck, Susanne Tom
Cheema, Manjinder S.
Sanchez‑Mut, Jose V.
Moksa, Malgorzata M.
Carles, Annaick
Brodie, Nick I.
Journal Title
Journal ISSN
Volume Title
Publisher
Epigenetics & Chromatin
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.
Description
Keywords
MeCP2, Isoforms, Chromatin, Rett syndrome
Citation
Martínez de Paz, A., Khajavi, L., Martin, H., Claveria‑Gimeno, R., Dieck, S. T., Cheema, M. S., … Ausió, J. (2019) MeCP2-E1 isoform is a dynamically expressed, weakly DNA-bound protein with different protein and DNA interactions compared to MeCP2-E2. Epigenetics & Chromatin, 12. https://doi.org/10.1186/s13072-019-0298-1