A Novel Mecp2 Y120D 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

Anna Gandaglia, Elena Brivio, Sara Carli, Michela Palmieri, Francesco Bedogni, Gilda Stefanelli, Anna Bergo, Barbara Leva, Chiara Cattaneo, Lara Pizzamiglio, Marco Cicerone, Veronica Bianchi, Charlotte Kilstrup-Nielsen, Ilda D’Annessa, Daniele Di Marino, Patrizia D’Adamo, Flavia Antonucci, Angelisa Frasca, Nicoletta Landsberger

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)4838-4854
Number of pages17
JournalMolecular Neurobiology
Volume56
Issue number7
DOIs
Publication statusPublished - Jul 1 2019

Keywords

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

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'A Novel Mecp2 <sup>Y120D</sup> 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'. Together they form a unique fingerprint.

Cite this