de Paz, Alexia MartinezKhajavi, LeilaMartin, HeleneClaveria-Gimeno, RafaelDieck, Susanne TomCheema, Manjinder S.Sanchez-Mut, Jose V.Moksa, Malgorzata M.Carles, AnnaickBrodie, Nick I.Sheikh, Taimoor I.Freeman, Melissa E.Petrotchenko, Evgeniy V.Borchers, Christoph H.Schuman, Erin M.Zytnicki, MatthiasVelazquez-Campoy, AdrianAbian, OlgaHirst, MartinEsteller, ManelVincent, John B.Malnou, Cecile E.Ausio, Juan2019-11-292019-11-292019-11-292019-10-1010.1186/s13072-019-0298-1https://infoscience.epfl.ch/handle/20.500.14299/163474WOS:000496990000002Background: 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.Genetics & Hereditymecp2isoformschromatinrett syndromerett-syndromemutationsrevealsexon-1identificationdeficiencysequencecomplexgenesbindstext::journal::journal article::research article