Identification of transcription regulatory mechanisms mediating host responses to the microbiota in the intestinal epithelium

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  • March 21, 2019
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  • Davison, James
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
Abstract
  • All organisms must detect and respond to environmental pressures or else risk death. For animals, these pressures include maintaining symbiosis with the microorganisms that dominate their world. Over the course of evolution, these intimate microbial relationships have influenced animal tissue function and cellular identities. Microbial impact on animal cellular identity is most salient in the intestinal epithelia which interfaces with the largest concentration of microorganisms on any animal surface. In this dissertation, I explore the genomic and transcriptional regulatory mechanisms that mediate microbial tuning of intestinal epithelial identities. The collection of microorganisms that reside in the intestine (the intestinal microbiota), contribute to host physiology by facilitating energy harvest, tuning metabolic programs, promoting epithelial barrier function, promoting epithelial renewal and promoting immune system development. In addition to these important roles in health, intestinal microbiota have been implicated in a growing number of human diseases associated with loss of intestinal epithelial identity and function like Inflammatory Bowel Diseases. The microbiota impact intestinal epithelial function in part by regulating the expression of hundreds of genes in intestinal epithelial cells. Extensive research has identified the downstream physiological consequences of this transcriptional control. However, there remains a significant gap in our understanding of the upstream molecular mechanisms that mediate these host transcriptional responses. I identified that zebrafish transcription factor Hepatocyte nuclear factor 4 alpha (Hnf4a) specifically binds and activates a microbiota-suppressed intestinal epithelial transcriptional enhancer. Deletion of this transcription factor in zebrafish revealed that it activates nearly half of the genes that are also suppressed by the microbiota, suggesting that its activity is negatively regulated upon microbiota colonization. Experiments from intestinal epithelial cells from gnotobiotic mice revealed that microbiota colonization is associated with genome wide reductions in HNF4A DNA occupancy. Similarly, HNF4A binding sites were associated with hundreds of microbiota-activated or microbiota-inactivated enhancers. These data indicate HNF4A may be an important regulator in the host response to the microbiota. Together, these data provide a novel genomic mechanism for understanding how the microbiota tune intestinal epithelial transcription programs and may contribute to Inflammatory Bowel Diseases.
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  • In Copyright
Advisor
  • Cyr, Douglas
  • Sethupathy, Praveen
  • Brennwald, Patrick
  • Rawls, John
  • Major, Michael
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2017
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