Student Theses and Dissertations

Date of Award

2021

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Heintz Laboratory

Abstract

While epigenetic dynamics in mitotic differentiating cells have been characterized in depth, little is known about how postmitotic neurons regulate their chromatin state. Modulation of transcription through the regulation of accessibility of transcription factor binding sites is essential for the regulation of migration, synapse formation and terminal differentiation. Although 5-hydroxymethylcytosine (5hmC), the oxidized form of 5-methylcytosine, accumulates to high levels in neuronal lineages and refines the genomic binding of MeCP2, the functional consequences of 5hmC deposition in differentiating neurons have not been determined. We report high resolution characterization of the genomic landscape of developing postmitotic Purkinje neurons, confirm the relationship between 5hmC and gene expression and identify a novel class of genes that are demethylated in the absence of cell division. Deletion of the 5hmC writers Tet1, Tet2, and Tet3 from postmitotic Purkinje cells alters cytosine modification in regulatory domains, impairs gene expression, hinders developmental transitions, and causes hyper-excitability and increased susceptibility to excitotoxic drugs. These data demonstrate that 5hmC and the Tet proteins are required for terminal differentiation of Purkinje cells through demethylation of important regulatory regions. Our data, along with recent reports of the role of Tet proteins in neurodegeneration suggest an essential role in development and function of all neurons.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

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