Ancient Gut Genetic Core Program Finding May Lead to New Digestive Disease Therapies

Scientists from the Duke University School of Medicine have discovered a network of genes and genetic regulatory elements in the lining of the intestines that has stayed remarkably the same from fishes to humans. Many of these genes are linked to human illnesses, such as inflammatory bowel diseases, diabetes and obesity.

The research (“Genomic Dissection of Conserved Transcriptional Regulation in Intestinal Epithelial Cells”), which appears in PLOS Biology, marks fish as a model organism for studying how this old genetic information (covering over 420 million years of evolution) controls the development and dysfunction of the intestine.

“The intestinal epithelium serves critical physiologic functions that are shared among all vertebrates. However, it is unknown how the transcriptional regulatory mechanisms underlying these functions have changed over the course of vertebrate evolution. We generated genome-wide mRNA and accessible chromatin data from adult intestinal epithelial cells (IECs) in zebrafish, stickleback, mouse, and human species to determine if conserved IEC functions are achieved through common transcriptional regulation. We found evidence for substantial common regulation and conservation of gene expression regionally along the length of the intestine from fish to mammals and identified a core set of genes comprising a vertebrate IEC signature,” write the investigators.

“We define an IEC transcriptional regulatory network that is shared between fish and mammals and establish an experimental platform for studying how evolutionarily distilled regulatory information commonly controls IEC development and physiology.”

“Our research has uncovered aspects of intestinal biology that have been well conserved during vertebrate evolution, suggesting they are of central importance to intestinal health,” said John F. Rawls, Ph.D., senior author of the study and associate professor of molecular genetics and microbiology. “By doing so, we have built a foundation for mechanistic studies of intestinal biology in nonhuman model systems like fish and mice that would be impossible to perform in humans alone.”

According to Dr. Rawls, researchers for years have used animal models to collect information on intestinal epithelial cells that could help combat human diseases. But no one knew how alike these cells were across multiple species. He and colleagues took a comparative biology approach to address this issue.

Research associate Colin R. Lickwar, Ph.D., and the team obtained genome-wide data from intestinal epithelial cells in four species: zebrafish, stickleback fish, mouse, and human. Dr. Lickwar then created maps for each of the species that showed both the activity level of all of the genes and the location of specific regulatory elements that turned the genes on and off.

The group found a surprising amount of similarity between the different vertebrate species. Dr. Lickwar identified a common set of genes—labeled an intestinal epithelial cell signature—some of which had shared patterns of activity in specific regions along the length of the intestine. Many of these genes had previously been implicated in a variety of human diseases, and Drs. Lickwar and Rawls wanted to know if this conserved genetic signature was controlled by regulatory elements that might also be shared between species.

They took regulatory elements from fish, mice, and humans and put them into the zebrafish, which are transparent organisms. The scientists then looked under the microscope for color patterns to tell whether a green fluorescent protein or red fluorescent protein, which they had inserted along with the regulatory element, had been turned on in the intestine. They found that this was the case, indicating a very high level of conservation.

“Our findings suggest that intestinal epithelial cells use an ancient core program to do their job in the body of most vertebrates,” said Dr. Lickwar, who is lead author of the study. “Now that we have identified this core program, we can more easily translate results back and forth between humans and zebrafish.”