Microbial and Tissue-Specific Regulation of Gene Transcription in the Zebrafish Intestine

Animal physiology is directed by complex interactions between factors encoded in the animal’s genome and those encountered in their environment. The impact of these interactions on animal health is most evident in the intestine, where digestion and absorption of dietary nutrients occur in the presence of complex communities of microorganisms (microbiota). Interactions between gut microbiota and animal hosts are known to regulate immune and metabolic homeostasis and also contribute to a spectrum of human diseases, including the inflammatory bowel diseases, obesity, and malnutrition. Physiologic responses in eukaryotic cells are often mediated by changes in gene transcription that are specific to the cell type and the stimulus. The specificity of the transcriptional response is determined by targeted alterations in chromatin accessibility and the resulting interactions between specific transcription factors (TFs) and open chromatin at DNA cis-regulatory modules (CRMs). A fundamental challenge in the study of host-microbiota interactions is to understand how host cells interpret dynamic microbial signals within the context of tissue-specific regulatory networks to evoke appropriate transcriptional responses. The amenability of the zebrafish to in vivo imaging, transgenesis, and gnotobiotic manipulations provides exciting opportunities to address these questions. We initially conducted a detailed in vivo structure-function analysis of CRMs at the zebrafish angptl4 locus that mediate intestine-specific expression and microbial suppression. We are now seeking to define the TFs that recognize those CRMs and the microbial cues that might regulate their activity. We are also using genomic approaches to extend these studies to CRMs at other microbiota-responsive genes to understand the regulatory logic governing the host’s transcriptional and physiologic responses to the microbiota. The objective of this work is to improve our understanding of intestinal physiology as a dynamic integration of genome-encoded and environmental factors.