New genomics tool boosts diabetes research

CAMBRIDGE, Mass. — Researchers have developed a method for scanning the entire human genome to successfully map the location of key gene regulators, mutated forms of which are known to cause type 2 diabetes. The research marks the first time that human organs, in this case the pancreas and liver, have been analyzed in this way and opens the door to similar studies of other organ systems and diseases.

The work, published in the Feb. 27 issue of the journal Science, could lead to new approaches for developing medications and assessing a person’s genetic risk to this and other conditions, says Richard Young, a scientist at Whitehead Institute for Biomedical Research and lead researcher on the project.

Key to understanding the relationship between genes and disease are gene regulators called transcription factors, proteins that bind to specific areas of the genome and act to switch genes on and off. To discover how a specific transcription factor might contribute to a particular disease, scientists must locate each point in the genome where the transcription factor adheres and identify the individual genes it controls. Using conventional tools, it might take a single scientist a lifetime to do this for just one transcription factor. Yet humans have over 1,000 transcription factors and dozens of these have been linked to diseases.

“We developed an efficient gene-scanning technology so we could map genome binding sites for many transcription factors in a human organ,” says Duncan Odom, a postdoctoral fellow at Whitehead Institute and lead author of the paper. “This allows us to identify the sets of genes where transcription factors act as switches and to learn how defects in these switches might cause disease.”

In October 2002, a team led by Young, who also is a professor of biology at Massachusetts Institute of Technology, reported in Science on a technology used to identify how over 100 transcription factors were associated with the yeast genome, reducing the amount of time it would ordinarily take to do this from centuries to months. In this new study, Young’s team demonstrates that a modified version of this technology also can be used to scan human tissue.

The researchers applied this technology to several transcription factors that reside in the pancreas and liver and were known to be associated with type 2 diabetes, but just how they contributed to the disease was unknown. They discovered that one of the transcription factors, called HNF4, controls about half of all the genes needed to make the pancreas and liver. This suggests that without HNF4, these organs could not function normally, which is particularly relevant to diabetes because the pancreas produces insulin and loss of insulin production causes the disease.

HNF4 seems to contain many of the mutations that predispose a person to type 2 diabetes, the scientists say. “This new evidence explains why defects in the HNF4 transcription factor can lead to diabetes,” says Young. “Even a small loss of HNF4 function could affect the health of the pancreas because this regulator is associated with so many important genes in this organ.”

Now that we understand HNF4’s role, Young suggests researchers might be able to develop medications that modify the activities of mutated forms of HNF4, which could possibly prevent diabetes in some at-risk individuals. Also, these findings could enable scientists to create methods for analyzing an individual’s genetic profile to determine exactly that person’s risk level.

“This really changes your whole perspective,” says Graeme Bell, professor of biochemistry and molecular biology at University of Chicago and co-author on the paper. “Before we were just looking at these conditions one gene at a time. Now we can see the whole playing field, and more importantly, we can see the players.”

These findings go beyond diabetes and offer a whole new way of approaching research on many diseases, Young adds. “There are many human diseases associated with mutations in transcription factors, including cancer, hypertension and immunological and neurological disorders. Discovering how transcription factors regulate genes in various human organs should continue to provide clues to the causes of disease and offer new approaches for therapy.”

Citation

Odom, D. T., Zizlsperger, N., Gordon, D. B., Bell, G. W., Rinaldi, N. J., Murray, H. L., ... & Young, R.A. (2004). Control of pancreas and liver gene expression by HNF transcription factors. Science, 303(5662), 1378-1381.