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

• Main Authors: Alexia Martínez de Paz, Leila Khajavi, Hélène Martin, Rafael Claveria-Gimeno, Susanne Tom Dieck, Manjinder S. Cheema, Jose V. Sanchez-Mut, Malgorzata M. Moksa, Annaick Carles, Nick I. Brodie, Taimoor I. Sheikh, Melissa E. Freeman, Evgeniy V. Petrotchenko, Christoph H. Borchers, Erin M. Schuman, Matthias Zytnicki, Adrian Velazquez-Campoy, Olga Abian, Martin Hirst, Manel Esteller, John B. Vincent, Cécile E. Malnou, Juan Ausió
• Format: Article
• Language: English
• Published: BMC 2019-10-01
• Series: Epigenetics & Chromatin
• Subjects: MeCP2; Isoforms; Chromatin; Rett syndrome
• Online Access: http://link.springer.com/article/10.1186/s13072-019-0298-1

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.