Date of Award
Fall 2022
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Genetics
First Advisor
Sestan, Nenad
Abstract
The human brain is widely acknowledged to be one of the most complex, mysterious, and intriguing structures on earth. Crucial to expanding our understanding of this fascinating organ is exploring the evolutionary processes that culminated in the development of the human brain, but also understanding what happens when the development or function of the brain are altered, as in the case of neurodevelopmental or neuropsychiatric diseases. While some interesting examples of human-specific protein coding genes with roles in brain development or disease have been identified,1–3 it has been hypothesized that changes in non-coding, regulatory regions have played a primary role in human brain evolution.4 Thus, there is a striking need to explore the role of gene regulatory mechanisms in brain evolution and disease. Here I will summarize my work that has contributed to this goal.In chapter 2, I describe work that has explored the role of a ZBTB18-dependent regulatory network in governing neocortical projection neuron diversity, connectivity, and evolution. Increased diversity of neocortical excitatory projection neurons and the emergence of the corticospinal tract (CST) and corpus callosum (CC) are hallmarks of mammalian brain evolution. To illuminate the underlying regulatory mechanisms, we utilized genome-wide transcriptomic and epigenetic sequencing to identify cell type- specific regulatory elements with features unique to mammals, including ZBTB18, a critical postmitotic transcriptional regulator of certain key enhancers and genes, such as Cux2 and Bcll1b/Ctip2. We identified notable conservation of the ZBTB18 binding motif and its downstream regulatory network among eutherians. Together, this work uncovered key elements of the gene regulatory network governing neocortical projection neuron diversity, connectivity, and evolution. In chapter 3, I present work that has expanded our knowledge of the boundaries between post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). Despite striking amounts of genetic and transcriptomic overlap, PTSD and MDD are distinct disorders with very different etiopathology. In this work, I utilize post-mortem transcriptomic data to analyze alternative splicing patterns that may reveal notable differences between PTSD and MDD at the level of gene regulation. This work revealed that PTSD and MDD are more distinct in their splicing profiles than their expression profiles, and that particular genes previously implicated in PTSD, such as GRM5, show differential splicing patterns between PTSD and control brains. Here we also utilize long-read, full-transcript RNA-seq to confirm isoform-specific gene expression in PTSD and MDD and to continue exploring the molecular and gene-regulatory mechanisms that distinguish these two neuropsychiatric disorders. Together, this work expands our understanding of the complex gene regulatory mechanisms that underlie brain evolution and disease.
Recommended Citation
Muchnik, Sydney Keaton, "The role of gene regulatory mechanisms in brain evolution and neuropsychiatric disease" (2022). Yale Graduate School of Arts and Sciences Dissertations. 745.
https://elischolar.library.yale.edu/gsas_dissertations/745
