Clock affects RNA splicing

New findings help explain how the 24-hour light-dark cycle influences physiological processes -- by regulating how RNA molecules are cut-and-pasted after they are transcribed, according to a study published online today (20 October) in Nature.

Arabidopsis thaliana
Image: Wikimedia commons, Sui-setz

"We already knew that [the circadian clock] had a big effect on transcription rates, where you get cyclical gene expression," said molecular biologist linkurl:Isaac Edery;http://lifesci.rutgers.edu/%7Emolbiosci/faculty/edery.html of Rutgers University, who did not participate in the study. "What's interesting about this paper is it's making the first link between the circadian timing mechanism and broad regulation at the level of alternative splicing."Most organisms have a built-in clock, which regulates many biochemical, physiological, and behavioral processes on a roughly 24-hour schedule. Alterations to these circadian rhythms are known to contribute to a variety of ailments, from sleep disorders and aging to diabetes and cancer. Researchers have identified many "clock" genes whose expression follows this cycle and affect a variety of biological functions. In search of other genes that may be involved in the clock network, plant physiologist linkurl:Marcelo Yanovsky;http://www.leloir.org.ar/index.php/en/component/contact/83-jefes-de-laboratorio/34-dr-marcelo-yanovsky.html of the Leloir Institute Foundation in Buenos Aires, Argentina, and his colleagues examined a collection of mutant Arabidopsis plants. Screening approximately 30,000 mutants for abnormal growth rhythms, the team found one that followed a 27-hour cycle. The mutant gene in those plants turned out to code for an enzyme called protein arginine methyl transferase 5 (PRMT5).PRMT5 is known to transfer methyl groups to arginine in histones. Because histones play a role in regulating gene expression, the group immediately suspected that the gene was affecting how often clock genes were transcribed -- a common theme in circadian regulation. Indeed, an expression microarray revealed that, in PRMT5 mutants, the most over-expressed gene was the well known clock gene pseudo response regulator 9 (PRR9). Over-expression of PRR9 usually leads to shorter circadian periods, however, not longer. Closer examination revealed that the mutant plants were actually over-expressing a truncated form of PRR9, and expressed less of the full length protein, suggesting PRMT5 was not affecting gene expression, but RNA splicing -- a post-transcriptional process. By modifying the machinery that cuts introns out of messengerRNA transcripts -- a process that can result in a variety of mature mRNA molecules from each gene -- PRMT5 was affecting the clock at an entirely different level.The results "emphasize a new layer of regulation in how the clock is both built and does its work inside of a cell," said molecular biologist linkurl:Steve Kay;http://biology.ucsd.edu/faculty/kay.html of the University of California, San Diego, who was not involved in the research. Furthermore, because PRMT5 is itself regulated by the circadian cycle, "it forms yet another conceptual feedback loop within with circadian network," he said.To see how widespread PRMT5's effects were on the splicing machinery, Yanovsky and his colleagues did a genome-wide screen for alternative mRNA transcripts. Interestingly, they found less than 1 percent of genes were affected. "Most of the genes throughout the genome were correctly spliced," Yanovsky said. Looking in more detail at the subset of genes that were affected, the team found that many of them had weak 5' splice sites -- the connection between the splicing machinery and the immature transcript could be easily broken. Thus, the mutant PRMT5 seemed to somehow strengthen that bond and encourage the alternative splicing of those transcripts.Because PRMT5 is a highly conserved protein from yeast to humans, the group also explored this mechanism in Drosophila. Indeed, they found that PRMT5 mutants showed disruptions in circadian rhythms and a variety of mRNA transcripts exhibited altered splicing."The fact that it's shared in plants and flies really tells us that it's fundamental to how the clock works," said Edery. This is particularly interesting in light of the fact that very few clock components are shared by plants and animals, Yanovsky added. "By the clock regulating this key enzyme [that] can regulate the expression and processing of many different genes, [organisms] can regulate many different physiological processes," he said. "And that's probably something that was useful in different times throughout evolution."S.E. Sanchez, et al., "A methyl transferase links the circadian clock to the regulation of alternative splicing," Nature, doi:10.1038/nature09470, 2010.
**__Related stories:__***linkurl:No circ. clock for reindeer?;http://www.the-scientist.com/blog/display/57213/
[11th March 2010]*linkurl:DNA damage resets body clock;http://www.the-scientist.com/blog/display/54357/
[21st February 2008]*linkurl:Immune system, circadian clock linked;http://www.the-scientist.com/news/display/53380/
[17th July 2007]

Clock affects RNA splicing

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