New method identifies human microRNA targets

January 28, 2004

Tags: Bartel LabRNA

CAMBRIDGE, Mass. — Research into the mechanics of microRNAs, tiny molecules that can selectively silence genes, has revealed a new mode of gene regulation that scientists believe has a broad impact on both plant and animal cells. Fascinated by the way microRNAs interfere with the chemical translation of DNA into protein—effectively silencing a targeted gene—scientists are exploring the role that these miniature marvels play in normal cell development and how they might be used to treat disease.

A critical component of understanding how microRNAs work in humans has been identifying which genes’ microRNAs silence and what processes they control. In a recent study, scientists identified more than 400 human genes likely targeted by microRNAs, taking an important step toward defining the relationship between microRNAs and the genes they target, including those linked to disease and other vital life functions.

“MicroRNAs are one of the many types of regulatory molecules important in determining which genes are on or off in a particular cell,” says David Bartel, a scientist at Whitehead Institute for Biomedical Research and professor of biology at Massachusetts Institute of Technology. “Understanding what they do may provide the answers to some unsolved mysteries of gene regulation and help us better understand human biology and disease.”

In 2003, Bartel and Chris Burge, an assistant professor of biology at MIT, developed a computational method able to detect the microRNA genes in different animals. Using this method, they estimated that microRNAs constitute nearly 1 percent of genes in the human genome, making microRNA genes one of the more abundant types of regulatory molecules.

Bartel and Burge then set out to apply a similar approach to defining the relationship between microRNAs and the genes they target. Last month in the journal Cell, their labs reported that they have created a new computational method, called TargetScan, which does just that.

For each microRNA, TargetScan searches a database of messenger RNAs (mRNAs)—chemical messages that transcribe DNA into protein—for regions that pair to portions of the microRNA, and assigns a score to the overall degree of pairing that could occur between the microRNA and each mRNA. Those mRNAs that have high scores conserved in three or more organisms are predicted as targets of the microRNA.

Using this method, the team identified more than 400 genes in the human, mouse and rat genomes likely to be regulated by microRNAs. In addition, TargetScan predicted an additional 100 microRNA targets that are conserved in humans, mice, rats and the pufferfish.

According to Burge, 70 percent of targets predicted by TargetScan are likely to be authentic microRNA targets and the experimental data in the paper supports that a majority of their predictions are correct.

Early research has shown that some microRNAs impact genes that serve as master regulators—genes that play a pivotal role in the regulation of other genes. This has been seen in plants, and in a few cases in flies and worms, where microRNAs contribute to the extraordinary turning on and off of genes required to transform an embryo into an adult. Results from the Cell study suggest that mammalian microRNAs are doing more.

“In contrast to what we see for plant microRNAs, many mammalian microRNAs do not appear to be primarily involved at the upper levels of the gene regulatory cascades,” says Bartel. “They also appear to be operating at lower levels to regulate the expression of a diverse set of genes.”

In the process of developing TargetScan, the researchers also found which parts of the microRNA are most important for ensuring that the microRNA silences the correct target, suggesting that a certain segment of the microRNA is more important than other parts in making this discrimination. Such insights, useful for finding the natural targets of the microRNAs, will also be helpful for those trying to use microRNA-like molecules for drug therapies.

“A detailed understanding of this mechanism will aid in the engineering of new small RNAs that regulate particular target genes while avoiding undesired side effects,” says Burge. “MicroRNAs or related molecules could potentially be used to therapeutically manipulate gene expression in cases where malfunctioning genes contribute to disease.”

A next step, says Burge, is additional work to improve the team’s computational methods. These improvements will enable the researchers to generate more accurate and comprehensive predictions for which genes are regulated by microRNAs, and further elucidate the biological roles of the microRNA-mediated gene regulation.

Written by Melissa Withers.

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