Date of Award
Doctor of Philosophy (PhD)
The development of organisms relies on complex spatial and temporal patterning of gene expression to define cell types and facilitate their functions. Cis-regulatory elements in our genome are responsible for the control of gene expression across tissues and cell types. Regulation of these elements themselves depends on a balance of activation and repression through epigenetic modifications and molecular regulatory components. Disruption of cis-regulatory element control is emerging as a cause of neurodevelopmental disease. An important contributor to gene regulation in development is methylation of cytosine in DNA, disruption of which has been associated with disease. Notably, while all cell types employ methylation at CG dinucleotides to control gene expression, mammalian neurons contain uniquely high levels of non-CG DNA methylation that are critical for proper nervous system function. MeCP2, the protein associated with Rett syndrome, in turn binds to non-CG methylation to regulate gene expression. Defining how non-CG methylation accumulates in neurons and is read out by MeCP2 will improve our understanding of the unique gene-regulatory environment in these cells and can begin to decipher the molecular underpinnings of neurodevelopmental disorders. Here, I explore the role of gene expression and genome architecture in establishing patterns of non-CG methylation in neurons and highlight emerging mechanistic insights into how non-CG methylation and MeCP2 control transcription through neuronal enhancers. I define a nested pattern of methylation by which highly-methylated, mega-base scale topologically-associated domains contain genes of high methylation, which themselves contain enhancers of high methylation. MeCP2 represses enhancers found in these methylation-enriched domains, with the strongest repression occurring for enhancers located within genes repressed by MeCP2. I show that loss of methylation-dependent repression of enhancers can drive changes in gene expression in models of disease. Finally, I outline preliminary findings identifying upstream and downstream mechanisms of enhancer regulation through MeCP2 and DNA methylation. These insights provide clues as to how the distinctive epigenome in neurons facilitates the development and function of the complex mammalian brain.
Chair and Committee
Harrison W. Gabel
Kristen Kroll, Ting Wang, Andrew Yoo, Shiming Chen,
Clemens, Adam, "Understanding the Roles of DNA Methylation and MeCP2 in Neuronal Enhancer Control" (2021). Arts & Sciences Electronic Theses and Dissertations. 2309.