Etchegaray and Gao Labs Examine Gene Regulation and Its Role in Preventing Gastrointestinal Diseases

Assistant Professor Jean-Pierre Etchegaray and Professor Nan Gao, of Rutgers University–Newark’s Department of Biological Sciences, are cellular and molecular biologists whose work examines the underlying causes of health and diseases.

Recently they teamed up to decipher how genes that respond to infection are regulated in cells within the epithelial lining of the intestine, which may impact future treatments for pathogenic bacteria such as Salmonella and conditions such as inflammatory bowel disease.

Their research, which was funded for two years by a $430K grant from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), was recently published in the journal Proceedings of the National Academy of Sciences (PNAS).

Etchegaray and Gao were co-corresponding authors on the paper and conceived the project by combining their individual expertise in epigenetic and transcriptional research (Etchegaray), and gastrointestinal and cell biology (Gao). Doctoral students and a senior scientist from their teams—Edward Gonzalez and Dahui Wang from Etchegaray’s lab, and Yue Liu from Gao's—played integral roles in the study and were co-first authors of the PNAS article.

"Jean-Pierre is really strong in epigenetics and stem-cell biology, which is an expertise our department didn’t have before, and so with our collaboration we can take a really interdisciplinary approach to our research. It’s a very good fit,” said Gao. “And our Ph.D. students and senior scientist are very important to the progression of this project.”

There are fundamental biological questions unanswered regarding the role of these genes to our health.

This collaborative research focuses on the epithelial lining of the human intestine, which is composed of different types of cells with specific roles, including those responding to stressors in the gastrointestinal tract such as pathogens, inflammatory agents and chemical toxins. The Etchegaray and Gao teams have set out to understand the role of specific gene networks in these intestinal cells and the underlying mechanisms that regulate these genes’ behavior in either enabling or resisting these immune-system stressors.

According to Etchegaray, prior research by scientists had confirmed the importance of a family of genes called TET1, TET2 and TET3 encoding for enzymes that function as important epigenetic regulators capable of controlling gene expression.

"These enzymes, or epigenetic regulators, can turn “on” and “off” hundreds, even thousands of genes,” said Etchegaray, referring to a process known as “transcription”, and this regulation is instrumental to maintain health and protect against disease.

For their study, the Etchegaray and Gao’s labs confirmed that the TET3 gene is the most prominently expressed gene in cells of the intestinal epithelial lining. They also created a genetically modified mouse model using sophisticated genetic techniques, then deleted the TET3 gene in specific cells responsible for immune response within this epithelial lining to see if the mice would be more susceptible to pathogens and chemical toxins.

They found that deficiency of this TET3 gene correlates with compromised immune response and regeneration of intestinal epithelia, deciphering a role for this TET enzyme as an essential regulator of immune defense and stress-response genes in the intestine.

The ultimate goal, which the teams hope to achieve in future research, is to understand how these TET enzymes control the gene expression, also known as transcription, of these intestinal immune-response genes.

There are fundamental biological questions unanswered regarding the role of these genes to our health,” said Etchegary. “We’ve done an important epigenetic analysis telling us that TET3 controls the expression of specific genes involved in protecting the intestinal epithelial lining, and when TET3 is genetically deleted, the expression of stress-response genes is being deregulated. But what are the actual biochemical mechanisms by which these enzymes can change the expression of specific gene sets? How are these enzymes doing this? These mechanisms can be very sophisticated. We’re looking at these questions for future phases of our research.”

Etchegary and Gao Lab graduate students

The two teams working on the project have strong ties to Rutgers University.

Etchegaray, who is from Chile, completed his Ph.D. at the Rutgers Robert Wood Johnson Medical School in Piscataway before doing post-doctoral research at the University of Massachusetts and Harvard Medical Schools. Gonzalez, the first author of this manuscript, completed his B.S. in Biological Sciences at Rutgers–New Brunswick before joining the Etchegaray lab as a master’s student in 2019 and being accepted into the Ph.D. program at RU-N. Wang, who hails from China and did his B.S. at the University of California, Irvine, started in Etchegaray’s lab as a master’s candidate in 2021 and was then quickly promoted to the Ph.D. program. And Liu, who has a medical degree from China, was a research scientist at Rutgers–New Brunswick for 15 years before moving to Gao’s lab five years ago as lab manager.

Gonzalez has the distinction of being supported by the G-RISE Program, which is an institutional grant awarded to RU-N from the National Institute of General Medical Sciences (NIGMS) of the NIH that provides stipend, tuition and research support to Ph.D. students to increase diversity in the biomedical science research field. The Co-Program Directors of the grant are Professors Mauricio Delgado and Barry R. Komisaruk. Etchegaray and Gao are both mentors in the G-RISE Program.

Etchegaray feels fortunate to be working with such talented and driven students and colleagues, and fully appreciates the collaboration between the two labs, seeing it as essential to producing world-class scientific discovery.

“Our Ph.D. students and research scientist bring their own passions, expertise and skills to our research. They help build the lab and strengthen the concepts. Without them, there is no lab. It’s teamwork. That’s been our culture,” said Etchegaray. “And while my and Professor Gao’s expertise could not be more different, there’s a very productive synergy to address fundamental biological questions. We anticipate many more projects and papers to come out of this collaborative research.”


Top Photo (L-R): PNAS paper authors Maciej Jeziorek, Edward Gonzalez, Sheila Bandyopadhyay, Assistant Professor Jean-Pierre Etchegaray, Dahui Wang, and Professor Nan Gao (missing: Yue Liu)

Bottom Photo (L-R): Yue Liu, Dahui Wang and Edward Gonzalez