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The Alternate Way to Splice RNA

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  • Title: Group Leader, Laboratory of Post-transcriptional Regulatory Networks, MRC Laboratory of Molecular Biology
  • Education: PhD, Rockefeller University, 2004
  • Recommended by: Juan Valcarcel

Jernej Ule may not be directly studying human diseases right now, but his work may someday help researchers trying to understand and develop treatments for disease. At his new lab at the MRC Laboratory of Molecular Biology in Cambridge, UK, Ule is developing new assays and tests to study how alternative splicing of RNA occurs. To complement his study of splicing and RNA binding proteins, Ule is also creating software to analyze data from new splicing microarrays and is adapting his research to use the ultra-high-throughput sequencers coming off the production line. The goal, says Ule, is to be able to understand the rules that RNA-binding proteins, especially the neuron-specific alternative splicing factor called Nova, follow to determine how RNA is spliced.

When Ule began his PhD, he was interested in cellular networks, especially those involved in signal response. Ule then realized that studying protein phosphorylation, as he had been, is not easily adaptable to study on a large scale. And, at the time, RNA was just hitting it big. “I was looking for other fields where I could basically ask the same questions but in a vaster timescale,” Ule says.

Ule now uses that large-scale approach to study how Nova affects RNA splicing. “Once we’ve starting these genome-wide studies we could see that [Nova’s] activity can be mapped in a very systematic way. Once you know where the protein binds the RNA, you know what is going to be the outcome of this binding,” says Ule. “It was quite unexpected, actually.”

In a recent Nature paper, Ule describes such a map that predicts the outcomes from binding. “We could say, for example, if a protein binds 50 nucleotides downstream of an alternative exon, we will know that will enhance inclusion of that exon. But if it binds within the exon, it will cause skipping exclusive of the exon,” Ule says. Ule is now building on that work to study how protein-RNA networks affect cell signal response on different timescales.

Looking ahead

Though Ule isn’t currently studying any diseases, he thinks RNA will play a role in understanding and treating disease. “I think the RNA level in protein-RNA interactions might help us to devise new pathways of RNA-based therapeutics that would affect how the proteins interact with the RNA,” he says. “I hope that in six years we would be able to get to something more practical.”

Publications of note

As a postdoc, Ule studied Nova using a custom exon junction microarray. Ule’s advisor, Robert Darnell, worked with an array company to analyze the data, but they couldn’t get the stringency needed. “The data was lying around and it wasn’t clear if it was very useful or not. It was very exciting for me — not being a trained bioinformatician — to just play around with the data and actually go back and forth from experiment to data analysis and come up with a simple algorithm that truly worked and that predicted 50 new alternative targets of Nova,” says Ule, whose results were published in Nature Genetics.

These new exons led them to discover that Nova regulates a set of RNAs, all related to neuronal inhibition. That was the basis of an article in which Ule describes a map predicting RNA splicing events based on where Nova binds.

And the Nobel goes to ...

If Ule were to win the Nobel Prize, he’d like it to be for something he hasn’t done yet. “It would have to have a very important medical relevance —something that would have helped millions of people in the future in the way that diseases are treated,” says Ule.

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