Johnson, Brian S., Zhao, Ying-Tao, Fasolino, Maria et al. (10 more authors) (2017) Biotin tagging of MeCP2 in mice reveals contextual insights into the Rett syndrome transcriptome. Nature Medicine. pp. 1203-1214. ISSN 1078-8956
Abstract
Mutations in MECP2 cause Rett syndrome (RTT), an X-linked neurological disorder characterized by regressive loss of neurodevelopmental milestones and acquired psychomotor deficits. However, the cellular heterogeneity of the brain impedes an understanding of how MECP2 mutations contribute to RTT. Here we developed a Cre-inducible method for cell-type-specific biotin tagging of MeCP2 in mice. Combining this approach with an allelic series of knock-in mice carrying frequent RTT-associated mutations (encoding T158M and R106W) enabled the selective profiling of RTT-associated nuclear transcriptomes in excitatory and inhibitory cortical neurons. We found that most gene-expression changes were largely specific to each RTT-associated mutation and cell type. Lowly expressed cell-type-enriched genes were preferentially disrupted by MeCP2 mutations, with upregulated and downregulated genes reflecting distinct functional categories. Subcellular RNA analysis in MeCP2-mutant neurons further revealed reductions in the nascent transcription of long genes and uncovered widespread post-transcriptional compensation at the cellular level. Finally, we overcame X-linked cellular mosaicism in female RTT models and identified distinct gene-expression changes between neighboring wild-type and mutant neurons, providing contextual insights into RTT etiology that support personalized therapeutic interventions.
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Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | This is an author-produced version of a paper accepted for publication. Uploaded with permission of the publisher/copyright holder. Further copying may not be permitted; contact the publisher for details |
Keywords: | Alleles,Animals,Biotin,Biotinylation,Cerebral Cortex/cytology,Female,Gene Expression Profiling,Gene Knock-In Techniques,Genotype,Methyl-CpG-Binding Protein 2/genetics,Mice,Mosaicism,Mutation,Mutation, Missense,Neurons/metabolism,Phenotype,Rett Syndrome/genetics,Transcriptome/genetics |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Biology (York) The University of York > Faculty of Sciences (York) > Psychology (York) |
Depositing User: | Pure (York) |
Date Deposited: | 06 Oct 2017 15:45 |
Last Modified: | 07 Nov 2024 01:27 |
Published Version: | https://doi.org/10.1038/nm.4406 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1038/nm.4406 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:122204 |
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