At Huntsman Cancer Institute (HCI), a collaborative culture is essential to research efforts. Focusing on various aspects of a single problem—cancer—scientists in the 24 HCI labs work in teams to advance knowledge of the disease and use their discoveries to develop new treatments for it. An effort currently underway provides just one example of this culture at work.

A team of HCI investigators studies how a process called DNA methylation works in the normal development of cells and how the process differs in cancer cells. Improper methylation of genes is associated with many kinds of cancer. Colon cancer is among them, and it’s the area of interest in the Jones Lab, headed by David Jones, PhD, associate professor of oncological sciences at the University of Utah. Leukemia and bloodborne cancers are also associated with improper methylation, and the Trede Lab, headed by Nikolaus Trede, MD, PhD, assistant professor of pediatrics at the University of Utah, studies them. Both researchers use zebrafish to study genes associated with these cancers. The Cairns Lab, headed by Brad Cairns, PhD, associate professor of oncological sciences at the University of Utah, has developed methods to analyze DNA methylation patterns in zebrafish, using microarray techniques which can examine the methylation status of every gene in the genome.

“Two years ago, it would take an expert researcher two weeks to examine the DNA methylation status of a single gene. However, microarray has dramatically changed that pace,” says Cairns. “The microarray involves placing tens of thousands of genes in separate locations on a glass slide, allowing us to examine them individually using a laser. Using microarray technology, we can examine ten thousand genes in one month. This allows us to rapidly identify genes methylated during normal development or during cancer and to be very comprehensive in our searches.

Cells and entire organisms use methylation as part of the gene regulation mechanism during normal development. Typically, methylation acts like a switch that turns off a given gene until the appropriate time in development, when actions within the cell remove the methylation and allow the gene to function. This in turn allows the cell to develop properly. Previous studies looked at particular genes and found differing methylation patterns during various phases of embryonic development.

Methylation patterns of specific genes also differed during development of the gut and of specialized cells such as T lymphocytes, white blood cells essential to immune defenses.

“The zebrafish is an incredibly powerful model system,” says Trede. “The fish are genetically very closely related to humans, and can therefore be used to establish versatile models of human disease. Given their rapid development and small size, they are ideally suited for drug screens to identify compounds that may be used to treat human patients.”

The three HCI labs are attempting to establish the normal methylation patterns of about 13,000 genes in the zebrafish genome during development of both embryos and specialized cells. With that knowledge, the scientists can begin to tease out the incorrect methylation patterns that contribute to leukemia, colon cancer, and developmental defects.

“When the DNA sequence of a gene is mutated, there’s no way to fix it,” says Jones. “You can circumvent the gene, but you can’t repair it. But in cancers associated with improper methylation, if we can develop a drug that corrects the methylation pattern, the gene would behave normally again.”

HCI has already run a clinical trial of one drug that targets DNA methylation, but it affects both normal and abnormal methylation patterns. “We’re studying the details of the methylation process and refining our knowledge so we can narrow the target for future generations of cancer drugs,” says Jones.

Working together, these scientists hope to discover how methylation is established and how it goes wrong in cancer. The end goal: they want to learn how to interfere with or reverse incorrect methylation to create effective new drugs, positioning HCI to be one of the leading centers for a new type of cancer treatment.