Date of Award

5-7-2024

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Modulation of gene expression is fundamental to the exceptional complexity and diversity of cells in the nervous system. Within that last decade, evidence has emerged that neurons utilize unique forms of DNA methylation to regulate transcriptional programs, with multiple types of neurons displaying high levels of cytosine methylation in a non-CG context compared to non-neural cells. This non-CG methylation primarily occurs at CA dinucleotides (mCA) and is read out by methyl-CpG binding protein 2 (MeCP2). Inactivation of MeCP2 results in Rett Syndrome (RTT), a severe neurodevelopmental disorder, while overexpression of MeCP2 results in MeCP2 duplication syndrome, an autism spectrum disorder. MeCP2 has been identified as a critical reader of mCA and regulates transcription of long neuronal genes that are embedded in regions of high mCA. Both MeCP2 and mCA remarkably increase postnatally in the developing mammalian brain. Recent studies have identified that mCA patterns are highly cell-type specific, but how this methylation is read out by MeCP2 to dictate cell-type-specific transcriptional programs remains poorly understood. Here, I discuss the unique challenges to transcriptional regulation in the developing nervous system and how the mCA-MeCP2 pathway contributes to that process, particularly to cell-type-specific transcription. I then systematically analyze the effects of loss of MeCP2 on distinct neuronal cell types. I show that the methylation level of a population of neurons determines the magnitude of dysfunction when MeCP2 is lost. I find evidence for both shared and distinct transcriptional regulation by MeCP2 across different cell types and identify enhancer elements as important sites of MeCP2 regulation to control cell-type-specific transcriptional programs. Finally, I provide evidence that MeCP2 and mCA are involved in the maturation and maintenance of stable transcriptomic subtype identities and discuss ongoing studies to follow up this exciting finding. These analyses provide a significant advance in our understanding of how MeCP2, along with mCA, regulate transcription within distinct types of neurons and allow for the specialization of neurons to drive the complex functions of the nervous system.

Language

English (en)

Chair and Committee

Harrison Gabel

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