Genomic dissection of conserved transcriptional regulation in intestinal epithelial cells

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Author summary The epithelium lining the intestine is an ancient animal tissue that serves as a primary site of nutrient absorption and interaction with microbiota. Its formation and function require complex patterns of gene transcription that vary along the intestine and in specialized intestinal epithelial cell (IEC) subtypes. However, it is unknown how the underlying transcriptional regulatory mechanisms have changed over the course of vertebrate evolution. Here, we used genome-wide profiling of mRNA levels and chromatin accessibility to identify conserved IEC genes and regulatory regions in 4 vertebrate species (zebrafish, stickleback, mouse, and human) separated from a common ancestor by 420 million years. We identified substantial similarities in genes expressed along the vertebrate intestine. These data disclosed putative conserved transcription factor binding sites (TFBS) enriched in accessible chromatin near IEC genes and in regulatory sites with accessibility restricted to IECs. Fluorescent reporter assays in transparent zebrafish showed that these regions, which frequently lacked sequence conservation, were still capable of driving conserved expression patterns. We also found a highly conserved region near mammalian and fish hes1 sufficient to drive expression in a specific population of IECs with active Notch signaling. These results establish a platform to define the conserved transcriptional networks underlying vertebrate IEC physiology.






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Lickwar, CR, JG Camp, M Weiser, JL Cocchiaro, DM Kingsley, TS Furey, SZ Sheikh, JF Rawls, et al. (2017). Genomic dissection of conserved transcriptional regulation in intestinal epithelial cells. PLOS Biology, 15(8). p. e2002054. 10.1371/journal.pbio.2002054 Retrieved from

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John F. Rawls

James B. Duke Distinguished Professor

We seek to understand how the intestinal microbiome contributes to vertebrate physiology and disease. To that end, we leverage complementary zebrafish and mouse models to study the integrative physiology of host-microbiome interactions. This work has identified novel and conserved mechanisms by which intestinal bacteria regulate dietary fat metabolism and systemic innate immunity. We also apply genomic approaches in these animal models to understand the transcriptional regulatory pathways utilized by the intestinal epithelium to mediate host responses to the microbiome. Using this approach, we have identified mechanisms of transcriptional and chromatin regulation that have been conserved during vertebrate evolution and also contribute to modern human diseases such as the inflammatory bowel diseases, obesity, and diabetes. To further advance our understanding of obesity pathophysiology, we developed the zebrafish as a model system for studying adipose tissues and identifying new environmental and genetic regulators of adiposity. We are also engaged in translational research in humans and animal models to define microbial and metabolic determinants of obesity and efficacy of weight loss intervention. Grounded in comparative and integrative physiology, our research program has been effective in discovering ancient mechanisms of host-microbiome interaction that are conserved across animal taxa and contribute to the etiology of modern human diseases. These insights are advancing our understanding of host-microbiome relationships in vertebrate physiology and identifying novel therapeutic targets for human diseases ranging from inflammatory bowel disease to obesity to neurological disorders.

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