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February 20, 2014

Long non-coding RNAs help genes get out of the starting block faster

Elizabeth Tran

Elizabeth Tran 
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WEST LAFAYETTE, Ind. - Yeast can quickly adapt to changes in its environment with the help of molecules known as long non-coding RNAs, a Purdue study shows.

Elizabeth Tran, assistant professor of biochemistry, and her fellow researchers found that long non-coding RNAs prepare metabolic genes to be activated swiftly when baker's yeast needs to switch its source of energy from glucose - its main sugar source - to an alternative sugar, galactose.

The study is the first to link long non-coding RNAs with the timing of gene expression.

"The fact that long non-coding RNAs are involved in the timing of gene expression was totally unexpected," Tran said. "This opens up new and exciting challenges for the future of genomic research."

Long non-coding RNAs - ribonucleic acids that are longer than 200 nucleotides - are molecules that influence the expression of protein-coding genes in yeast, plants and mammals. They were first described in 2007, and the functions of the vast majority of these molecules remain unknown.

One suggested role of long non-coding RNAs in yeast was gene repression, but Tran's study showed the opposite is true: Long non-coding RNAs accelerate the activation of genes involved in galactose digestion when glucose is lacking in the environment.

Yeast with long non-coding RNA begin metabolizing galactose about 30 minutes quicker than yeast without - a significant time difference in an organism that replicates every 90 minutes.

"That quick shift could make the difference in survival," Tran said.

Over time, the level of galactose enzyme gene expression in yeast with and without long non-coding RNAs becomes the same, but "it's that initial burst of gene expression in response to the environment that may provide a significant evolutionary advantage," said Tran. She likened it to the edge a sprinter would gain over his opponents by propelling himself out of the starting block ahead of them.

"One reason the runner Usain Bolt is so fast is that he developed a technique of getting out of the block really quickly," she said. "Being able to do that means you can spread out your energy during the race - all because you started faster at the beginning."

Tran said that similar long non-coding RNAs might play a role in the timing of gene expression in humans as well. In mammals, they are often associated with genes that control growth and organ development, which require tight control of initiation timing.

"When a growing embryo has to make an arm, for example, that timing has to be incredibly precise," she said.

Humans contain upwards of 8,000 long non-coding RNAs, some of which have been linked to cancer, developmental diseases and cardiomyopathy and other non-DNA mutations in the genome. Tran said the chances are high that long non-coding RNAs play a role in human diseases, developmental defects and delays.

"Now the question becomes why long non-coding RNAs are so closely associated with development," Tran said. "Having opened up the possibility that they're linked to timing and not end level of gene expression is really key."

The paper was published online in PLOS Biology and is available at http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001715

The study was also featured in Nature's "Research Highlights" at http://www.nature.com/nature/journal/v504/n7478/full/504011c.html

The National Institutes of Health funded the research. 

Writer: Natalie van Hoose, 765-496-2050, nvanhoos@purdue.edu

Source: Elizabeth Tran, 765-496-3889, ejtran@purdue.edu 


ABSTRACT

Long Noncoding RNAs Promote Transcriptional Poising of Inducible Genes

Sara C. Cloutier 1; Siwen Wang 1; Wai Kit Ma 1; Christopher J. Petell 1; Elizabeth J. Tran 1, 2

1 Department of Biochemistry, Purdue University, West Lafayette, Indiana, United States of America

2 Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana, United States of America

E-mail: ejtran@purdue.edu

Long noncoding RNAs (lncRNAs) are a class of molecules that impinge on the expression of protein-coding genes. Previous studies have suggested that the GAL cluster-associated lncRNAs of Saccharomyces cerevisiae repress expression of the protein-coding GAL genes. Herein, we demonstrate a previously unrecognized role for the GAL lncRNAs in activating gene expression. In yeast strains lacking the RNA helicase, DBP2, or the RNA decay enzyme, XRN1, we find that the GAL lncRNAs specifically accelerate gene expression from a prior repressive state. Furthermore, we provide evidence that the previously suggested repressive role is a result of specific mutant phenotypes, rather than a reflection of the normal, wild-type function of these noncoding RNAs. To shed light on the mechanism for lncRNA-dependent gene activation, we show that rapid induction of the protein-coding GAL genes is associated with faster recruitment of RNA polymerase II and reduced association of transcriptional repressors with GAL gene promoters. This suggests that the GAL lncRNAs enhance expression by derepressing of the GAL genes. Consistently, the GAL lncRNAs enhance the kinetics of transcriptional induction, promoting faster expression of the protein-coding GAL genes upon the switch in carbon source. We suggest that the GAL lncRNAs poise inducible genes for rapid activation, enabling cells to more effectively trigger new transcriptional programs in response to cellular cues. 


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