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CRG's Valcárcel on an EU-Wide Effort to Strengthen Alternative-Splicing Research


Juan Valcárcel
Senior Scientist
Center for Genomic Regulation
Name: Juan Valcárcel
Title: Senior Scientist, Center for Genomic Regulation
Professional background: 2002-present, senior scientist, Center for Genomic Regulation, Barcelona, Spain; 1996-2002, group leader, gene expression program, European Molecular Biology Laboratory, Heidelberg, Germany; 1991-1995, postdoc, molecular medicine, University of Massachusetts Medical Center, Worcester.
Education: 1990 — PhD, molecular biology, Universidad Autónoma de Madrid, Spain; 1984 — BSc, biology and chemistry, Universidad de Santiago de Compostela, Spain.

When it comes to microarray platforms for alternative splicing research, Juan Valcárcel has tried it all. The 45-year-old senior scientist at the Center for Genomic Regulation in Barcelona has used Agilent-manufactured in-house designs, arrays created by ExonHit Therapeutics, as well as Affymetrix’s exon array platform to aid in his work.
Valcárcel is also involved in Eurasnet, a European Union-sponsored network of alternative-splicing researchers that has recently started an inter-laboratory, cross-platform comparison of splice-array platforms on the market. The team hopes to use its strength in numbers to negotiate better prices and more effective technologies with vendors.
To learn about this project and more, BioArray News spoke with Valcárcel this week.
Why are you interested in alternative splicing? Why have you decided to focus on this area, as opposed to something else, like methylation?
Well, [the] historical reason [is] that my PhD focused on the influenza virus. We found a mechanism of splicing regulation during the influenza infection. So this caught me; the idea of how gene expression can be regulated not at the transcriptional level but after the transcript is made. I decided to work on that for my postdoc and then afterwards when I founded this group.
Basically if you think of gene expression, most people think that the regulation happens whether or not you make a transcript, but the reality is very different. Now we know that probably 80 percent of human transcripts are alternatively spliced in ways that they produce different proteins.
This is a much unexplored area of how you can establish programs of gene regulation that are relevant for development, for cell differentiation, [and] for homeostasis. And the mechanisms behind this are not well understood. That’s the reason why we keep working on that.
What platforms have you used to do that?
We try to combine biochemistry with assays in cell culture and microarrays. We do a lot of in vitro assays with RNA and extracts or RNA and recombinant proteins to try and understand how splice sites become accessible or are hidden from the splicing machinery. We try to combine these biochemical assays with work in tissue culture, mostly in Drosophila or mammalian cells, and we do RNAi or transcription factors to try and understand which factors are relevant to regulation and how they work.
We combine these two aspects and then we try to integrate the microarrays within the analysis of mechanisms of regulation. For example, if we suspect that there is a factor that is responsible for some alternative splicing regulation, then we would try to see with microarrays which events change when you over-express or when you knock down the expression of this factor. From that, you can infer how the factor works. We always have to go back to in vitro and biochemical experiments to test these hypotheses.
We can also work the other way around. We can start from a biochemical result and then we can try to see whether a mechanism that we come up with is really general or not by using microarrays and cells in culture.

You are a deputy director forEurasnet, a European Union-created alternative splicing consortium. How was it created and what are its goals?



Eurasnet was started in January 2006 as a European Union-funded project, what they call a “network of excellence.” There was a call for a network of excellence on splicing regulation, probably reflecting the relevance that this field is getting, and the EU thought it would be good to integrate the efforts of different groups working on this.
The idea was to basically touch base and to exchange everything from reagents to protocols and to frequently meet to see how we could better collaborate. One of the most important components of this is that we want to establish platforms and move the technology further. Microarrays is one example, but we are working in several areas.
This type of technology-driven focus is very important for us. What we hope is that by working together on this we can get better technologies, we can share the know-how, and we also try to strike better deals with companies. If there are many of us and we are influencing the way this kind if research is conducted in Europe, then we should also have better opportunities with companies. That is another aspect.
There are different outreach activities of the network and one very important one is to reach the medical community. It is becoming clearer that many mutations affecting human disease are based on RNA processing and alternative splicing. More and more, medical diagnosis is based on RNA analysis rather than genomic analysis. This is one important community that we want to get in touch with and to help.
You told me recently that you are planning a cross-platform comparison study within Eurasnet. When will that commence?
Well, we were supposed to have the results of our cross-validation experiment by the end of February. I expect that to be completed within the next few weeks. Hopefully by the next annual meeting in April, we will make a decision on which companies we would like to approach and we will provide the information about what the result of the comparison was to all members of the network and anyone who is interested. For sure, we will have everything finished by the end of April.
On the microarray side, we hope to get out of the meeting with a clear idea of what platforms should be used for what application and also with a proposal to start negotiating with companies for better deals for European scientists that are interested in this topic.
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