MicroRNAs go from stop to start

MicroRNAs, noncoding RNAs widely thought to repress gene expression, can also perform the opposite role of activating translation, according to a study published online today in Science.

The study "makes us rethink how microRNA regulates genes," said Phillip Sharp of the Massachusetts Institute of Technology, who was not a coauthor. "By current dogma, all regulation is thought to be negative -- in cancer, immune responses, everything. This is not a small issue, and it's going to be debated."

MicroRNAs exert their effects by targeting messenger RNA, and, most researchers hold, repressing protein translation. However, a few previous studies have raised the possibility that microRNAs play an activating role, said Shobha Vasudevan of the Yale University School of Medicine, the lead author of the paper. One study reported that a microRNA found in the human liver increased replication of RNA of the Hepatitis C virus (HCV), presumably by activating gene expression.

Vasudevan and her colleagues stumbled upon the current findings while investigating how gene expression is activated. Their previous work had shown that adenylate/uridylate-rich elements (AREs), conserved sequences on many messenger RNAs, form a complex with two proteins to activate translation. Since these proteins are known to be involved in microRNA functioning, they examined the role of microRNA in translational activation by ARE. They found that the ability of AREs to associate with the two proteins depended on a microRNA (miR369-3).

They also found that miR369-3 activated translation only after the cell cycle stopped. During the cell cycle, while the cell was proliferating, the microRNA down-regulated translational activity, but upon cell-cycle arrest, it reversed its effect.

The group then examined two other microRNAs to see if this process occurred more widely. Both also demonstrated oscillation between regulation and activation over the course of the cell cycle.

Vasudevan noted that they do not yet understand the mechanism that differentially triggers activation or repression. Also, this oscillation is yet to be observed in vivo. "[Our study] opens up more avenues for research," she said, by "adding new functions to something previously described as a repressor."

Greg Hannon of the Cold Spring Harbor Laboratory, who was not involved in the work, agreed that future studies would have to determine the biochemical mechanism of this phenomenon and determine whether it occurs in vivo. Still, he said, the study "really changes the way we have to think about microRNA targets."

Jonathan Scheff
mail@the-scientist.com

Correction (posted Dec. 10): A previous version of this article mistakenly stated that microRNAs activate transcription instead of translation. The Scientist regrets the error.


Links within this article:

D. Steinberg, "MicroRNA Shows Macro Potential," The Scientist, June 16, 2003.
http://www.the-scientist.com/article/display/13871/

The Scientist Staff, "The RNA Conductome," The Scientist, Sept. 2007.
http://www.the-scientist.com/2007/10/1/55/1/

S. Vasudevan et al., "Switching from repression to activation: microRNAs can up-regulate translation," Sciencexpress, Nov. 29, 2007.
http://www.sciencexpress.org

Phillip Sharp
http://web.mit.edu/sharplab/

C.Q. Choi, "A New View of Translational Control," The Scientist, Dec. 5, 2005.
http://www.the-scientist.com/article/display/15897/

A. Goodman et al., "The Uncertain Future for Central Dogma," The Scientist, June 20, 2005.
http://www.the-scientist.com/article/display/15540/

C. Jopling et al., "Modulation of Hepatitis C virus RNA abundance by a liver-specific microRNA," Science, Sept. 2, 2005.
http://www.the-scientist.com/pubmed/16141076

S. Vasudevan and J. Steitz, "AU-rich-element-mediated upregulation of translation by FXR1 and Argonaute 2," Cell, March 23, 2007.
http://www.the-scientist.com/pubmed/17382880

Greg Hannon
http://gradschool.cshl.edu/hannon_.html