Biotin tagging of MeCP2 in mice reveals contextual insights into the Rett syndrome transcriptome
Autor: | Darren Goffin, Golnaz Vahedi, George Georgakilas, Janine M. Lamonica, Zhaolan Zhou, Yue Cui, Ying-Tao Zhao, Kathleen H. Wood, Tae Hoon Kim, Brian S. Johnson, Maria Fasolino, Daniel Bu, Yoon Jung Kim |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
congenital hereditary and neonatal diseases and abnormalities Cell type Genotype Methyl-CpG-Binding Protein 2 Mutation Missense Biotin Rett syndrome Biology General Biochemistry Genetics and Molecular Biology MECP2 Transcriptome Mice 03 medical and health sciences Rett Syndrome medicine Animals Missense mutation Biotinylation Gene Knock-In Techniques Gene Alleles Cerebral Cortex Neurons Genetics Mosaicism Gene Expression Profiling General Medicine medicine.disease Phenotype Gene expression profiling 030104 developmental biology Mutation Female |
Zdroj: | Nature Medicine. 23:1203-1214 |
ISSN: | 1546-170X 1078-8956 |
Popis: | 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. |
Databáze: | OpenAIRE |
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