“We hope that these findings will lead to a more comprehensive understanding of how CFTR gene dysfunction can cause such a wide range of disease, eventually enabling us to develop effective treatments for cystic fibrosis and other gastrointestinal diseases,” said lead author Thankam Paul, M.D., a pediatric gastroenterologist at Hasbro Children’s Hospital and assistant professor of pediatrics at The Warren Alpert Medical School of Brown University.

The CFTR protein resides in the surface of cells lining the digestive system, lungs and sweat glands. In normal cells, it acts as an ion channel that transports chloride into and out of cells. It also controls the regulation of other transport pathways regulating the passage of fluid and bicarbonate across cell membranes.

Previous research indicates that DNA sequence variations (or mutations) alone do not explain CFTR-related gastrointestinal disease patterns; rather, epigenetic modifiers, or changes that leave the gene’s sequence of DNA intact, influence CFTR expression.

Paul and colleagues sought to define regions within the CFTR gene that correlate with histone acetylation, a process that modifies DNA-packaging proteins. After identifying a region associated with acute acetylation of histone H4, one of the major core histones, they conducted further tests which linked this process to active intestinal CFTR expression and occupation by regulatory factors known as HNF1a, Cdx2 and Tcf4. The combined activity of these factors appears to modify the architecture of chromatin, the form in which DNA is packaged in the cell, leading to alterations of CFTR expression.

“Our findings suggest the therapeutic potential of histone modification strategies to treat CFTR-associated disease by selectively enhancing CFTR expression,” said Neal LeLeiko, M.D., Ph.D., study co-author and director of the division of gastroenterology, nutrition and liver diseases at Hasbro Children’s Hospital. He is also a professor of pediatrics at Alpert Medical School.

The study’s senior author was Martin J. Walsh, Ph.D., of Mount Sinai School of Medicine. Co-authors were Sanjeev Khurana, M.D., of Hasbro Children’s Hospital and Alpert Medical School, and SiDe Li, M.D., of Mount Sinai School of Medicine.

Hasbro Children’s Hospital (www.hasbrochildrenshospital.org) in Providence, RI, is the pediatric division of Rhode Island Hospital, the largest teaching hospital of The Warren Alpert Medical School of Brown University. A private, not-for-profit hospital, it is nationally recognized for its child protection program and Draw-A-Breath asthma and allergy initiative. It is also the home of the Injury Prevention Center, which aims to reduce accidental injuries in children, as well as the region’s only pediatric imaging center. The hospital has pioneered numerous procedures and is at the forefront of fetal surgery, orthopedics and pediatric neurosurgery. Hasbro Children’s Hospital is a member of the Lifespan health system.