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Mol Neurobiol. 2019 Jul;56(7):4838-4854. doi: 10.1007/s12035-018-1412-2. Epub 2018 Nov 6.

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.

Author information

1
Neuroscience Division, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy.
2
Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, International Max Planck Research School for Translational Psychiatry, 80804, Munich, Germany.
3
Department of Psychology, University of Toronto Mississauga, Mississauga, Ontario, L5L 1C6, Canada.
4
Department of Biotechnology and Life Sciences, University of Insubria, 21052, Busto Arsizio, VA, Italy.
5
Department of Molecular Oncology and Immunology, the Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands.
6
Department of Medical Biotechnology and Translational Medicine, University of Milan, 20100, Milan, Italy.
7
Istituto di Chimica del Riconoscimento Molecolare, CNR (ICRM-CNR), 20131, Milan, Italy.
8
Department of Informatics, Institute of Computational Science, Università della Svizzera Italiana, 6900, Lugano, Switzerland.
9
Neuroscience Division, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy. nicoletta.landsberger@unimi.it.
10
Department of Medical Biotechnology and Translational Medicine, University of Milan, 20100, Milan, Italy. nicoletta.landsberger@unimi.it.

Abstract

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.

KEYWORDS:

Chromatin accessibility; Chromatin binding; MeCP2; Mouse models; Rett syndrome

PMID:
30402709
DOI:
10.1007/s12035-018-1412-2

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