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Team Develops Technology That Identifies Defects in Organs Transcription Factors


A team of researchers from the Whitehead Institute for Biomedical Research has developed a way to scan an entire human genome and map the location of a mutated transcription factor linked to type 2 diabetes.

If verified by additional research, the study, which marks the first time that scientists have studied transcription factors in individual organs, might also lead to new ways for developing drugs and predicting risk for diabetes and other diseases.

Today, scientists trying to discern how an individual transcription factor contributes to a disease must first find each point on the genome to which the factor adheres, and identify the genes the factor controls. Traditional technology makes the process of identifying a single factor time-consuming and cumbersome. The fact that humans have more than 1,000 transcription factors — dozens of which have already been linked to diseases — has confounded many scientists.

As a result, the Whitehead team, led by Duncan Odom, developed a gene-scanning technology to map genome binding sites “for many transcription factors” in a human organ, according Odom. “This allows us to … learn how defects in these switches might cause disease.”

In October 2002, Richard Young, a co-author of the paper and Odom’s colleague at Whitehead, Young wrote about a technology that could identify how more than 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,” the authors said. In the new study, which appears in the Feb. 27 issue of Science, the researchers showed that a version of this technology can also be used to scan human tissue.

Studying several transcription factors that reside in the pancreas and liver and are linked with type 2 diabetes, Odom’s team found that one of the factors, HNF4, controls roughly half of all the genes needed to make the pancreas and liver.

“This suggests that without HNF4, these organs could not function normally,” the authors wrote, adding that a malfunctioning pancreas causes diabetes by failing to produce insulin.

“This new evidence explains why defects in the HNF4 transcription factor can lead to diabetes,” Young said in a statement. “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.”

Young suggests researchers may “now be able to develop medications that modify the activities of mutated forms of HNF4, which could possibly prevent diabetes in some at-risk individuals.” The team’s findings may also “enable scientists to create methods for analyzing an individual’s genetic profile to determine exactly that person’s risk level,” the team said.

“This really changes your whole perspective,” said Graeme Bell, professor of biochemistry and molecular biology at University of Chicago and co-author on the Science 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.”

— KL


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