MeCP2-E1 isoform is a dynamically expressed, weakly DNA-bound protein with different protein and DNA interactions compared to MeCP2-E2
Alexia Martínez de Paz,
Susanne tom Dieck,
Manjinder S. Cheema,
Jose V. Sanchez-Mut,
Malgorzata M. Moksa,
Nick I. Brodie,
Taimoor I Sheikh,
Melissa E. Freeman,
Evgeniy V. Petrotchenko,
Christoph H Borchers,
Erin M. Schuman,
John B. Vincent,
Cécile E. Malnou,
Posted 14 Aug 2018
bioRxiv DOI: 10.1101/392092
Posted 14 Aug 2018
MeCP2, a chromatin-binding protein associated with Rett syndrome, has two main isoforms, MeCP2-E1 and MeCP2-E2, with 96% amino acid identity 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 they may also have non-overlapping molecular mechanisms. However, differential functions of MeCP2-E1 and E2 remain largely unexplored. 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 turnover rates, binding dynamics, response to nuclear 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. Our findings provide insight into the functional complexity of MeCP2 by dissecting differential aspects of its two isoforms.
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