Abstract

The mammalian brain features a variety of cell types with distinct functions and properties. This cellular diversity is maintained by epigenomic regulation of gene expression. Neurons in particular express long genes and are uniquely enriched for non-CG methylation, especially methylation at CA dinucleotides (mCA). MeCP2, whose mutation results in Rett syndrome, regulates gene expression by binding to mCA. However, the function of this mCA-MeCP2 pathway in the regulation of fine-tuned neuronal gene expression programs has not been investigated. Here, we provide evidence that mCA-MeCP2 pathway plays a role in the maintenance of neuron type-specific gene expression programs at a high level of cellular resolution. We find that neuronal populations with greater global mCA levels display stronger gene dysregulation upon loss of MeCP2. Furthermore, we investigate the methylation patterns and intragenic enhancer repression driving overlapping and distinct gene regulation between neuron populations. We use epigenomic and spatial transcriptomic analyses to show that the mCA-MeCP2 pathway regulates genes that are repeatedly tuned to differentiate neuron types at high cellular resolution. These repeatedly tuned genes include spatially resolved gene expression programs important for vision-dependent specification of closely related cell types in L2/3 of the mouse primary visual cortex. We find that these repeatedly tuned genes feature characteristics predisposing them to regulation to MeCP2, including long gene length, numerous intragenic enhancers, and high mCA level. Our findings suggest that mCA and MeCP2 facilitate the cellular diversity of the mammalian brain through this regulation of repeatedly tuned long genes.

Committee Chair

Harrison Gabel

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Computational & Systems Biology)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

5-2-2024

Language

English (en)

Author's ORCID

0000-0001-8908-3065

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