The Role of Epithelial Transcription Factor Elf3 in Mediating Transcriptional Programs in Zebrafish

Abstract

Animals interact constantly with microorganisms in the external environment that have significant consequences for their development, physiology, and behavior. Microbes can have both positive and negative effects on host health; however, host tissues typically employ mechanisms to physically contain microbial communities to prevent infection and limit microbial interaction. Animal tissues like epithelial cells that line exposed body surfaces are crucial for mediating these interactions that protect the host from infection, inflammation, and other diseases. Epithelial and other animal cell types can adapt to microbial stimuli through regulation of gene expression programs that inform cellular identity and function. While our understanding of microbially regulated transcriptional programs continues to progress, our knowledge of the specific transcription factors (TFs) that mediate these transcriptional responses is of particular interest. In Chapter 1, I provide a historical review of approaches used to evaluate microbiota function in animal hosts as well as functional genomic approaches that allow researchers to decipher host-microbiota interactions in distinct tissues. In Chapter 2, I describe how we identified the epithelial specific transcription factor E-74 like ETS transcription factor 3 (Elf3) as a candidate mediator of host responses to microbiota. We found that it is commonly upregulated in the digestive tissues of zebrafish and mice that are colonized with a microbiome (CV) compared to germ-free animals (GF). Next, I generated elf3 mutant zebrafish alleles to test the role of Elf3 in larval physiology as well as mediating microbial interactions. Compared to wildtype larvae, elf3 mutants failed to mount an appropriate host immune response to microbes. Furthermore, elf3 mutant adults exhibited worse survival outcomes compared to wildtype animals and sporadically displayed signs of disease that included abnormal swimming behavior, ulcer development, and erythema. Histopathological evaluation of moribund elf3 mutants demonstrated the association between these clinical signs of poor health and swim bladder inflammation (aerocystitis). Based on these data, I conclude that Elf3 is a microbially responsive transcription factor that mediates host responses to microbes in larval zebrafish and protects against the development of swim bladder inflammation and other pathologies in adults. In the final chapter, I address the limitation of this work and propose future experiments that could further our understanding of the role of Elf3 in mediating host-microbiota interactions. Together this work adds an important new node to the gene regulatory network mediating host responses to microbiota and provides a new animal model of Elf3 deficiency as a resource for the field.