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

Martínez 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. (Universidad de Zaragoza) ; Abian, O. (Universidad de Zaragoza) ; Hirst, M. ; Esteller, M. ; Vincent, J.B. ; Malnou, C.E. ; Ausió, J.

Resumen: 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.

Idioma: Inglés

DOI: 10.1186/s13072-019-0298-1

Año: 2019

Publicado en: EPIGENETICS & CHROMATIN 12, 63 (2019), s13072-019-0298-1 [16 pp.]
ISSN: 1756-8935

Factor impacto JCR: 4.237 (2019)

Categ. JCR: GENETICS & HEREDITY rank: 41 / 177 = 0.232 (2019) - Q1 - T1

Factor impacto SCIMAGO: 2.449 - Molecular Biology (Q1) - Genetics (Q1)

Financiación: info:eu-repo/grantAgreement/EUR/ERC/NeuroRibo-743216
Financiación: info:eu-repo/grantAgreement/EUR/ERC-EPINORC-268626
Financiación: info:eu-repo/grantAgreement/ES/FIS/PI15-00663
Financiación: info:eu-repo/grantAgreement/EC/H2020/727264/EU/Development of a ncRNA DNA Methylation Kit for Treatment Guidance in Cancer of Unknown Primary/EPIPHARM
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/CB16-12-00312
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/CPII13-0017
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/RD12-0036-0039
Financiación: info:eu-repo/grantAgreement/ES/MEC/FPU13-3870
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BFU2013-47064-P
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BFU2016-78232-P
Financiación: info:eu-repo/grantAgreement/ES/MINECO/SAF2014-55000-R

Tipo y forma: Article (Published version)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)