Student Theses and Dissertations

Date of Award

2021

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Jarvis Laboratory

Abstract

Vocal learning is a rare, complex behavior which is a critical component of human spoken language acquisition. It is convergent across several independent lineages of birds and mammals, including songbirds and humans. The development of speech and song production in humans and songbirds is strikingly similar, though the molecular mechanisms underlying these similarities are not yet understood. Our lab has previously found convergently differentially expressed genes in the vocal learning circuitry of humans and song-learning birds relative to adjacent non-vocal motor circuits. Most notably, the RA song nucleus in the songbird is molecularly convergent with the human laryngeal motor cortex. What remains unknown, however, is how such striking molecular convergences came to be. One likely mechanism by which differential expression can be established in the brain is DNA methylation, an epigenomic signature that is canonically associated with transcriptional repression. In my thesis work, I examined whether this differential specialized gene expression in the zebra finch, one of the most well-studied songbirds, is associated with differential DNA methylation. To do so, I performed whole-genome bisulfite sequencing in the RA song nucleus and its adjacent non-vocal motor region. I found that the convergent specialized transcriptome in this nucleus is in part defined by DNA methylation in a subset of these genes. A significant proportion of downregulated genes in RA exhibit increased gene body methylation relative to the adjacent non-vocal motor region. I additionally profiled the potential writers and readers of DNA methylation in the zebra finch brain to explore mechanisms for establishing the methylome over development. Strikingly, I found that the de novo writer of DNA methylation, DNMT3A, is specifically upregulated in the RA relative to the surrounding arcopallium only at post-hatch day ~60, not earlier or in adulthood. These findings indicate that differential DNA methylation could be contributing to specialization of gene down regulation, and thereby influence circuit specializations of vocal learning brain circuits. This study represents the first unbiased, basepair-resolution, genome-wide analysis of DNA methylation in the songbird as well as one of the first brain methylome studies in a non-mammalian vertebrate. Understanding the genomic mechanisms for vocal learning in the songbird will expand our understanding of speech and language disorders in humans, especially those that are congenital.

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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