Contextual Insights into the Rett Syndrome Transcriptome

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Doctor of Philosophy (PhD)
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Cell & Molecular Biology
High-throughput sequencing
Rett syndrome
Molecular Biology
Neuroscience and Neurobiology
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Mutations in MECP2 are responsible for Rett syndrome (RTT), a severe X-linked neurological disorder characterized by loss of developmental milestones, intellectual disability and motor impairments. However, molecular insight into how these mutations affect the neuronal transcriptiome, disrupt neuronal function and contribute to RTT is impeded by the cellular heterogeneity of the mammalian brain. A comparison between gene expression changes in the striatum, hypothalamus, and cerebellum of MeCP2-null mice revealed that gene expression changes are distinct between different brain regions, which suggests that MeCP2 function should be understood in a cell type-dependent context. To accomplish this task, I generated and phenotypically characterized tagged knock-in mice bearing frequent RTT mutations in Mecp2 (T158M, R106W). Concurrently, I also developed a novel genetic system that allows the tag to be post-translationally modified with biotin in a cell type-specific manner. Altogether, these mice allow for molecular profiling of WT and mutant cortical neurons in the mammalian brain. MeCP2-dependent gene expression changes vary by age and cell type, and the degree of Pol II-mediated transcriptional changes genome-wide correlates with the severity of the RTT mutation. I also detected evidence that supports the post-transcriptional compensation of misregulated long genes, leading to a reinterpretation of prevailing thought within the RTT research field with regards to MeCP2 function. Finally, this genetic strategy circumvents genetic mosaicism associated with female mouse models of RTT and identifies functionally distinct transcriptional changes between neighboring WT and mutant neurons, therefore providing key insights into phenotypic severity between RTT-associated mutation types. By assessing RTT transcriptomes across various neuronal contexts, I propose a novel contextualized paradigm for MeCP2 function in neuronal cell types that not only hypothesizes how MeCP2 dysfunction leads to the cellular deficits that give rise to RTT-like phenotypes, but identifies novel transcriptional and post-transcriptional mechanisms that may be future therapeutic targets for RTT.

Zhaolan Zhou
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