doi:10.1186/s13072-019-0298-1engMartínez De Paz, A.Khajavi, L.Martin, H.Claveria-Gimeno, R.Tom Dieck, S.Cheema, M.S.Sanchez-Mut, J.V.Moksa, M.M.Carles, A.Brodie, N.I.Sheikh, T.I.Freeman, M.E.Petrotchenko, E.V.Borchers, C.H.Schuman, E.M.Zytnicki, M.Velazquez-Campoy, A.Abian, O.Hirst, M.Esteller, M.Vincent, J.B.Malnou, C.E.Ausió, J.MeCP2-E1 isoform is a dynamically expressed, weakly DNA-bound protein with different protein and DNA interactions compared to MeCP2-E2ART-2019-114916Background: 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.2019http://zaguan.unizar.es/record/8634210.1186/s13072-019-0298-1http://zaguan.unizar.es/record/86342oai:zaguan.unizar.es:86342info:eu-repo/grantAgreement/EUR/ERC/NeuroRibo-743216info:eu-repo/grantAgreement/EUR/ERC-EPINORC-268626info:eu-repo/grantAgreement/ES/FIS/PI15-00663info:eu-repo/grantAgreement/EC/H2020/727264/EU/Development of a ncRNA DNA Methylation Kit for Treatment Guidance in Cancer of Unknown Primary/EPIPHARMThis project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 727264-EPIPHARMinfo:eu-repo/grantAgreement/ES/ISCIII/CB16-12-00312info:eu-repo/grantAgreement/ES/ISCIII/CPII13-0017info:eu-repo/grantAgreement/ES/ISCIII/RD12-0036-0039info:eu-repo/grantAgreement/ES/MEC/FPU13-3870info:eu-repo/grantAgreement/ES/MINECO/BFU2013-47064-Pinfo:eu-repo/grantAgreement/ES/MINECO/BFU2016-78232-Pinfo:eu-repo/grantAgreement/ES/MINECO/SAF2014-55000-REPIGENETICS & CHROMATIN 12, 63 (2019), s13072-019-0298-1 [16 pp.]byhttp://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccess