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Helicos and Integromics Identify New Class of Short RNA in Human Cells

By Kevin Davies

July 28, 2010 | Spain’s sizzling summer continues: an historic triumph in the World Cup, a victory at Wimbledon, and for Madrid-based Integromics, its first paper in Nature.*

“Thanks to our analysis, we can detect a specific signal that is characteristic and forms a new species of RNA. This new class of RNA is short RNAs that are antisense to the genes, but are not generated by antisense transcription. This is the real novelty in the paper,” says Sylvain Foissac, bioinformatics research scientist at Integromics and co-author on the paper, published this week.

Foissac formerly worked at Affymetrix with Helicos scientist and lead author Philipp Kapranov. “They were sequencing short RNAs in human cancer cells and found a lot of data. [Kapranov] invited me to help take a look at them and do the analysis,” Foissac tells Bio-IT World.

“Helicos are the only ones who can provide single-molecule sequencing on the market. This makes the analysis special, because we’re monitoring RNA quantities.”

The new class of short RNA (sRNA, shorter than 200 nucleotides) molecules was first identified in sequencing experiments on HeLa cells, the famous cancer cell line. (The authors note wryly that the molecules were not identified in sequencing experiments conducted on an Illumina machine.) The sRNAs accumulate at the end of genes, precisely at the end of the 3’ UTR untranslated region. Foissac hypothesizes that they could be made by copying the messenger RNA transcript. “The copying mechanism would start from the polyA tail, generating transcripts that start from the 3’ end.”

Foissac believes he and his Helicos collaborators have identified “a new molecular pathway operating in human cells” for generating sRNA molecules. The RNAs are generated by RNA-dependent RNA polymerase.

“This has been reported in plants, yeast, etc., but never at such a scale in human cells,” says Foissac. “We found them in thousands of genes. For the first time, this mechanism is broadly used in cells.” The findings offer a new vision of transcriptional regulation and a bevy of new targets for understanding gene expression.

Foissac says that Integromics has built up considerable experience in the transcriptomics arena, which helped in the current project. “We know what is worth looking at,” he says. “We know what biologists expect. We focus on the end user. Next-gen sequencing is amazing, but it’s a bit like a GPS. Lots of data and positions, but you want to know more. With GPS, you want not just coordinates but you want to know where you are. Which country? Is there a gas station nearby?! With sequence data, we have millions of reads and genome locations, but we need to go further. We compare these positions with information we already have on a genome-wide scale -- exons, introns, and so on. Now we can process and connect this information, increase the meaning of the biological analysis.”

The Integromics analysis was part of a pilot project that should culminate in the commercial release of software for RNA sequencing analysis before the end of the year. “It’s amazing that while developing this product, we could get access to great data,” says Foissac. “We’re very confident that the product will be successful.”

Integromics commercial chief Imad Yassin notes that the Nature paper marks one of the first example of a software company receiving co-authorship on a paper involving next-gen sequencing data analysis, particularly in the single-molecule sequencing space. 

While the single-molecule sequencing platform of Pacific Biosciences is about to be tested in the hands of paying customers, Foissac insists that the Helicos platform is the only one capable of doing this analysis right now. “So far, to really sequence the molecules in real-time accuracy, Helicos is the only one who provides this, and it works,” says Foissac.

The Helicos paper took over one year from initial submission to finally seeing the light of day. The delay was chiefly to allow additional control experiments to be conducted by collaborators Stylianos Antonarakis and Bino John to demonstrate that the findings were not the result of reverse transcription artifact.

The paper appears at a crucial time for Helicos, which is trying to carve out a niche for itself in the increasingly competitive next-generation sequencing market. The authors conclude by suggesting that “the ability of [single-molecule sequencing] to detect novel RNAs without amplification-induced biases will provide biologists with a powerful tool for better understanding gene expression.”

*Kapranov P. et al. “New class of gene-termini-associated human RNAs suggests a novel RNA copying mechanism.” Nature July 29, 2010.

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