Gene-regulating Protein Reaches Multiple Disease Pathways

Genomic scientists at The Children’s Hospital of Philadelphia found strong evidence that the protein family, FOXA2, is a master regulator of genetically vulnerable pathways in multiple diseases.

Study leader Struan F.A. Grant, PhD, holder of the Daniel B. Burke Chair for Diabetes Research at The Children’s Hospital of Philadelphia, has long investigated the genetics of diabetes and obesity. In the current study, he focused on the Forkhead Box A transcription factor, referred to as FOXA2, which was already known to act in the liver in affecting glucose levels. Dr. Grant and colleagues started with the hypothesis that FOXA2 regulated molecular pathways that are 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,” Dr. Grant said.

This computational analysis leveraged data from a team led by co-author Klaus H. Kaestner, PhD, 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. ChIP-seq isolates the pieces of DNA that are bound by proteins such as transcription factors.

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, and further study of those pathways may point the way to various novel therapies.

Grant and colleagues published their study in the The Journal of Clinical Endocrinology & Metabolism.

Study funding came from the National Institutes of Health and the Ethel Brown Foerderer Fund for Excellence from CHOP.