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Type of Resource (primo): dissertations
Name: Personal
Name: Personal
Name: Personal
Name: Personal
Name: Personal
Name: Personal
Name: Corporate
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Note: thesis: Thesis (Ph. D.)--Brown University, 2026
Genre (aat): theses
Abstract: Transcriptional co-regulation, the coordinated regulation of gene sets, is essential for development, homeostasis, and environmental responsiveness. However, the precise mechanisms by which specific regions of the genome are targeted for co-regulation remain unknown. A critical question about gene regulation that has been outstanding for the last fifty years is: How are the right genes targeted at the right time for co-regulation? I have made significant progress addressing this important specificity question using two well-established model systems: dosage compensation and heat stress. The mechanism by which transcription factors achieve context-specific co-regulation remains poorly understood in these systems despite decades of research. Here, I identify specificity mechanisms by generating and integrating three-dimensional multi-omics data across two complementary regulatory systems: dosage compensation (Chapter 2) and the heat stress response (Chapter 3). I also build and test multiple classes of predictive machine learning models to predict which factors work combinatorially together to co-regulate genes spatially and temporally (Chapter 4). In Drosophila, the essential GA-binding pioneer transcription factors CLAMP and GAF compete for occupancy at shared GA-repeat motifs that differ by only one SNP, yet produce distinct transcriptional outcomes in different biological contexts. In male Drosophila cells, where dosage compensation is constitutively active, I demonstrate that CLAMP and GAF directly regulate largely mutually exclusive 3D chromatin contacts. CLAMP drives short-range loops linking high-affinity dosage compensation complex (DCC) binding sites with active, dosage-compensated housekeeping genes on the X chromosome. In contrast, GAF mediates longer-range loops between transcriptionally silent insulator regions specifically on the X-chromosome but not on autosomes. On autosomes, CLAMP and GAF regulate looping at different subsets of active regions. These findings reveal how differential transcription factor occupancy creates an X-chromosome-specific chromatin environment for dosage compensation. In female Drosophila cells, which lack active dosage compensation, I identify CLAMP as the first DNA-binding transcription factor that directly regulates heat stress-induced repression of constitutive genes through modulation of 3D chromatin looping. I determined that CLAMP represses approximately 75% of heat stress-repressed genes and functions through a specific insulator-remodeler complex composed of Ibf1/2, ZIPIC, and ISWI. Together, my thesis work demonstrates that pioneer transcription factor competition at shared binding motifs drives context-specific co-regulation through differential modulation of 3D chromatin architecture. Finally, I developed interpretable graph neural networks for our integrated multi-omic datasets to computationally dissect the regulatory logic underlying context-specific co-regulation (Chapter 4). My models identified a novel link between transcriptional enhancers and dosage compensation which generates many new hypotheses to test. Together, I have discovered new three dimensional mechanisms by which specific genes are co-regulated over space and time through transcription factor competition. Many SNPs linked to disease are located within transcription factor binding sites and my thesis work identifies new rules for co-regulation of genes that will allow us to predict how SNPs cause transcriptional dysregulation in the future and correct these defects.
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Subject (fast) (authorityURI="http://id.worldcat.org/fast", valueURI="http://id.worldcat.org/fast/02032663")
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