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RNA, or ribonucleic acid, is one of the two types of nucleic acids found in all living cells. The other is the well-known deoxyribonucleic acid, or DNA. RNA is important because it transmits genetic information from DNA to build the proteins, including enzymes, produced by cells. RNA molecules often receive chemical changes. Methylation, which helps RNA fold and function properly, is one of these changes. If certain RNA molecules are not methylated, they function poorly and can contribute to diseases such as cancer. Currently, much remains to be learned about the full scope and functions of RNA methylation, especially in humans. Bradley R. Cairns, PhD, and his lab at Huntsman Cancer Institute (HCI) are changing that.
The Cairns Lab developed a new technique to analyze RNA methylation. They chose a group of enzymes called RNA cytosine methyltransferases (RMTs) connected to cancer, infertility, and certain genetic disorders in humans. Here is an overview of the technique: Each cell contains thousands of different types of RNA molecules, and a specific RMT can bond with only a small percentage of them. The first step in a study of RNA methylation is to sort out and concentrate the precise target RNA molecules for a particular RMT, in a process called enrichment. Then the samples are analyzed using high-throughput RNA sequencing. An important feature of the new technique is that the results show precisely where on the RNA molecules methylation is occurring.
"Our novel technique gives us 200-fold enrichment of methylated RNA. Two-fold enrichment has been considered a great result in the past," said Vahid Khoddami, the study’s co-author and a member of the Cairns Lab. "In fact, for some RNA types, our enrichment is more than 700-fold.” These research results were published in the journal Nature Biotechnology.
"Our enrichment results were fantastic by themselves, but in the sequencing process we made another important discovery," Khoddami said. "After sequencing, the target cytosine in the modified RNA appeared instead as an alternative molecule, guanosine. After sequencing, you can look for these cytosine-to-guanosine changes and know you have the precise target—in a single experiment."
According to Khoddami, ten cytosine RMTs are known in humans, and only two of them have been partially characterized. "None of the other eight have been studied in the laboratory," he explained. "Previously we did not have the tools to analyze the RNA. Now we have beautiful tools," said Khoddami.
Cairns adds, "This new technique will allow the very rapid identification of the direct target RNAs for each human RMT, and we are excited about conducting that work." Through deeper understanding of what goes awry in cancer and other genetic disorders, HCI researchers show what’s possible in working toward better treatments and, one day, a cure.
Cairns is Senior Director of Basic Science at HCI, a Howard Hughes Medical Institute investigator, and is also a Professor and Chair of the Department of Oncological Sciences at the University of Utah. He also holds a Jon and Karen Huntsman Presidential Professorship in Cancer Research.
Khoddami was a doctoral candidate and is now a postdoctoral fellow in the Cairns Lab at HCI.