A Novel Mecp2Y120D Knock-in Model Displays Similar Behavioral Traits But Distinct Molecular Features Compared to the Mecp2-Null Mouse Implying Precision Medicine for the Treatment of Rett Syndrome
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MeCP2 is a fundamental protein associated with several neurological disorders, including Rett syndrome. It is considered a multifunctional factor with a prominent role in regulating chromatin structure; however, a full comprehension of the consequences of its deficiency is still lacking. Here, we characterize a novel mouse model of Mecp2 bearing the human mutation Y120D, which is localized in the methyl-binding domain. As most models of Mecp2, the Mecp2Y120D mouse develops a severe Rett-like phenotype. This mutation alters the interaction of the protein with chromatin, but surprisingly, it also impairs its association with corepressors independently on the involved interacting domains. These features, which become overt mainly in the mature brain, cause a more accessible and transcriptionally active chromatin structure; conversely, in the Mecp2-null brain, we find a less accessible and transcriptionally inactive chromatin. By demonstrating that different MECP2 mutations can produce concordant neurological phenotypes but discordant molecular features, we highlight the importance of considering personalized approaches for the treatment of Rett syndrome.
KeywordsMeCP2 Rett syndrome Mouse models Chromatin accessibility Chromatin binding
We are extremely grateful to Giovanni Tonon and Simona Segalla (San Raffaele Scientific Institute) for their helpful technical suggestions. Part of this work was carried out in ALEMBIC, an advanced microscopy laboratory established by IRCCS Ospedale San Raffaele and Università Vita-Salute San Raffaele.
A.G and N. L conceptualized and designed most of the study. P.D-A and F.A. assisted the design and realization of the behavioral and electrophysiological studies, respectively. A.G., E.B., A.B., B.L., C.C., S.C., G.S., L.P., V.B., F.B., M.P., and M.C. conducted the experiments, prepared most of the figures, and revised the manuscript. A.F. helped with statistical analysis of data. N.L. wrote the manuscript with the assistance of A.F. D.D-M, I.D., and C.K-N assisted in interpreting and discussing results.
This work was mainly supported by the Italian parents’ association “pro RETT ricerca” to N.L. Financial support was from Fondazione Telethon, Italy (Grant no. GGP16015 to F.A.). Functional experiments were supported by the Italian Ministry of Research and Education program “FIRB giovani” 2010, protocol number RBFR10ZBYZ. Fondazione Veronesi (Milan, Italy) provided additional funding to F.B.
Compliance with Ethical Standards
Research involving animals was performed in accordance with the European Community Council Directive 2010/63/UE for care and use of experimental animals; all the protocols were approved by the Italian Minister for Scientific Research and by the San Raffaele Scientific Institutional Animal Care and Use Committee in accordance with the Italian law.
Conflict of Interest
The authors declare that they have no conflict of interest.
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