Endocrine-Related Protein Found to Be Master Regulator in Other Important Diseases

Newswise — Philadelphia, Sept. 16, 2014 – Investigating a protein known to be involved in regulating human glucose levels, genomic scientists found that this factor has a broader reach than first thought, acting on key gene pathways involved in cardiovascular, neuropsychiatric, and cancer-related diseases, in addition to its role in endocrine traits.

“We found strong evidence that this protein family, FOXA2, is a master regulator of genetically vulnerable pathways in multiple diseases,” said study leader Struan F.A. Grant, Ph.D., a genomics expert and holder of the Daniel B. Burke Chair for Diabetes Research at The Children’s Hospital of Philadelphia. Further study of those pathways may point the way to various novel therapies.

Grant and colleagues published their study online in the August 2014 issue of The Journal of Clinical Endocrinology & Metabolism, following early online publication on May 30.

This computational analysis leveraged data from a team led by co-author Klaus H. Kaestner, Ph.D., of the Perelman School of Medicine at the University of Pennsylvania, and used two important tools of next-generation genomic analysis: chromatin immunoprecipitation and massively parallel sequencing, together abbreviated as ChIP-seq. Relying on the fact that gene-regulating proteins such as transcription factors bind to DNA, ChIP-seq isolates the pieces of DNA that are bound by a particular protein.

Researchers then pass those fragments through automated sequencing machines to pinpoint and inventory the regions of the genome that specific transcription factors occupy. This knowledge allows investigators to better understand how transcription factors may activate or repress genes along important biological networks.

Grant has long studied genetics of diabetes and obesity, and in 2006 discovered the gene region with the strongest known effect on type 2 diabetes. In the current study, the Grant and Kaestner teams focused on the Forkhead Box A transcription factor, referred to as FOXA2.

Because FOXA2 was already known to act in the liver in affecting glucose levels, Grant and colleagues started with the hypothesis that FOXA2 regulated molecular pathways important in endocrine biology.

As they performed their analyses, the researchers found that FOXA2 proteins acted on sites in the genome that contained genes affecting endocrine-related traits such as glycemic levels, although not type 2 diabetes. They also found strong genome occupancy patterns associated with cardiovascular traits such as lipid levels, as well as with neuropsychiatric traits and cancer.

“FOXA2 appears to function as a master regulator for over a hundred other transcription factors, so it may play an outsized role in human health and disease,” said Grant. He added that many of these other transcription factors may in turn be fruitful candidates for researchers investigating disease pathways, and ultimately may allow scientists to discover targets for potential new treatments.

“Genome-Wide Analyses of ChIP-Seq Derived FOXA2 DNA Occupancy in Liver Points to Genetic Networks Underpinning Multiple Complex Traits,” The Journal of Clinical Endocrinology & Metabolism, volume 99, issue 8, published online May 30, 2014. http://doi.org/10.1210/jc.2013-4503

In addition to his position at CHOP, Grant also is on the faculty of the Perelman School of Medicine at the University of Pennsylvania. Co-authors with Grant and Kaestner were Andrew D. Wells, Ph.D., and Matthew E. Johnson, Ph.D., from CHOP; and Jonathan Schug, Ph.D., from Penn. Study funding came from the National Institutes of Health (grant P30DK19525) and the Ethel Brown Foerderer Fund for Excellence from CHOP.

About The Children’s Hospital of Philadelphia: The Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children’s Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program receives the highest amount of National Institutes of Health funding among all U.S. children’s hospitals. In addition, its unique family-centered care and public service programs have brought the 535-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu.