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Study uncovers clues to cystic fibrosis gene dysfunction and gastrointestinal disease
Date:12/13/2007

PROVIDENCE, R.I. A new study by researchers at Hasbro Childrens Hospital, the pediatric division of Rhode Island Hospital, and Mount Sinai Hospital, New York, offers new insight into the role that the cystic fibrosis gene plays in the development of gastrointestinal disease.

The cystic fibrosis transmembrane conductance regulator (CFTR) gene codes for a protein also known as CFTR. Mutations of this protein are associated with cystic fibrosis (CF) and a range of digestive diseases, such as inflammation of the pancreas, that can be severe and debilitating and can occur even in patients without CF. Yet the underlying mechanism by which CFTR gene dysfunction causes disease is poorly understood, limiting potential treatment options.

In the December 15th issue of the Biochemical Journal, scientists report the discovery of a new regulatory element in a region of the CFTR gene that can control the genes expression in the gastrointestinal tract. They also identified three important and active regulatory factors at this site that are known to control major aspects of intestinal cell regulation, including cell differentiation and growth.

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 Childrens 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 genes 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 Childrens Hospital. He is also a professor of pediatrics at Alpert Medical School.


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Contact: Jessica Collins Grimes
jgrimes2@lifespan.org
401-432-1328
Lifespan
Source:Eurekalert

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