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article imageNew Study Lends Insight Into How Genomes Work

By Bob Ewing     Dec 27, 2007 in Science
Cells keep a close watch over the transcriptome – the totality of all parts of the genome that are expressed in any given cell at any given time. Researchers teamed up to peel back another layer of transcriptional regulation and gain new insight.
A new study conducted by researchers at the Salk Institute for Biological Studies and the University of Missouri-Kansas City has uncovered another layer of transcriptional regulation and provides new insight into how genomes work.
The transcriptiome is the totality of all parts of the genome that are expressed in any given cell at any given time and this is a process over which cells keep very close observation.
There are two basic processes that are involved in order to convert the genetic blueprint into molecular building blocks; one is transcription which copies the information from DNA into RNA transcripts and takes place in the cell’s nucleus and the other is translation where the RNA serves as a template to manufacture proteins outside the nucleus.
The image that accompanies this article shows a growth-arrested embryo from a mutant Arabidopsis plant that contains a genetic lesion in a gene encoding an essential part of the exosome. The embryo is overlaid on a genome browser image of tiling expression data from an intergenic region that exhibits strong upregulation of a cluster of novel tandem repeat-associated, exosome-regulated transcripts.
It is essential for the transcripts to undergo a strict mRNA surveillance which will degrade defective, obsolete and surplus transcripts, before they can guide protein synthesis or take on regulatory functions.
"We found evidence for widespread exosome-mediated RNA quality control in plants and a 'deeply hidden' layer of the transcriptome that is tightly regulated by exosome activity," says Joseph R. Ecker Ph.D., professor in the Plant Biology Laboratory and director of the Salk Institute Genomic Analysis Laboratory.
The work of the exosome is to chew things up and thus the team had to inactivate this multi-unit complex to bring its otherwise invisible substrates to the fore. They were then able to comb the transcriptional landscape for hitherto unseen peaks of transcripts that now were untouched by the degrading force of the exosome complex and came up with a genome-wide atlas of Arabidopsis exosome targets.
"Our careful design and rigorous validation of the system for conditionally and quickly inactivating the exosome turned out to be really crucial for homing in on its RNA targets," explains Dmitry A. Belostotsky of the University of Missouri-Kansas City. "On the other hand, genome-wide analyses of permanent genetic mutations often produce a complex mixture of direct and indirect effects, making it very hard to untangle. Thus, we think our strategy has a broadly-applicable value."
"From a genomics perspective it really allowed us to visualize what information from the genome is actually expressed," adds co-first author Brian D. Gregory, Ph.D., a postdoctoral researcher in Ecker's lab. "When you knock down exosome activity, you see changes in the transcriptome that are not visible under any other circumstance."
It has been the common notion that the exosome plays a central role in bulk RNA turnover, the researchers say, so they expected to find the levels of all transcripts increasing when they inactivated the exosome complex.
"But not everything is going up, instead the exosome mechanism seems to be very tightly regulated," says Ecker. "We didn't see regions that are known to be silenced to go up; instead we found a very specific group of transcripts that are regulated in this way."
There are regular protein-coding RNAs, RNA processing intermediates and hundreds of non-coding RNAs, all present and the vast majority has not yet been described.
"These strange transcripts are associated with small RNA-producing loci as well as with repetitive sequence elements," says Gregory. "They are under very tight regulation by the exosome, but we still don't know exactly what this means."
"It is likely that these RNAs that are usually 'deeply hidden' become important for genome function or stability under some circumstances", adds co-first author Julia Chekanova, an assistant at the University of Missouri-Kansas City. "We need to do more work to figure out what these circumstances are."
Researchers who also contributed to the study include post-doctoral researchers Ravi Kumar, Ph.D. and Tanya Hooker, Ph.D. at the University of Missouri – Kansas City, post-doctoral researchers Sergei V. Reverdatto and Pinghua Li at the State University of New York at Albany, graduate student Qian Peng, bioinformaticist Huaming Chen, postdoctoral researchers Junshi Yazaki, Ph.D and Jose Alonso, Ph.D., all at the Salk Institute, post-doctoral researcher Nikola Skiba, Ph.D., at Havard Medical School, and post-doctoral researcher Vladimir Brukhin and professor Ueli Grossniklaus, Ph.D., at the University of Zürich, Switzerland.
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