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A Fresh Look at Differential Expression

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  • Title: Associate Professor, University of Massachusetts Medical School
  • Education: PhD, Medicine Utrecht University, The Netherlands, 1997
  • Recommender: Marc Vidal

Sometimes taking a backward approach to a common problem can yield surprising results. Such is the thought process of Marian Walhout, who is using a roundabout way of studying differential gene expression in C. elegans.

The standard operating procedure for this kind of gene expression research is usually a method centered on transcription factors, wherein one starts with a transcription factor of interest and then proceeds to locate where it binds in the genome. Walhout is going the other way around by taking a piece of DNA and then attempting to find out the factors that bind to that piece of DNA.

"Technically this approach is different because we use a method called the yeast one-hybrid system, whereas the method that has been used a lot is the yeast two-hybrid system, so it is different from what anybody else is doing in the field," she says. "I'm not saying one-hybrid is better or is more important, but that it's complementary — and this is what we need, different methods that can tackle the problem in different ways and from different angles. And that's our unique approach to the problem that no one is doing."

After finishing what she calls a "hard core" PhD in the biochemistry of transcription in her native Holland, Walhout was eager to find the best place to do a postdoc in the US; Marc Vidal, who has a lab at the Dana-Farber Cancer Institute, came highly recommended. "Marc works in yeast, and that I liked, and he was interested in understanding the human genome from the view of protein-protein interactions, and that I liked, even though it was a little enigmatic to me at the time," she says. "Then we met and really hit it off. We are completely like-minded in science, and both of us benefited tremendously from working with each other, so it was highly synergistic, which was just fantastic."

Looking ahead

Walhout says that ultimately her lab has two big genome-related goals for the long term. The first is to go one or two orders of scale more than what they are currently able to do in C. elegans. "We are further automating our pipeline and we are almost there, so in three years or so we should have much more comprehensive networks that we can study and get the idea of the principle for how they control gene regulation within the worm," she says.

And if she can get the funding, Walhout says she would also like to apply the approach she has developed to humans. "Because now we have set up all the technology in the worm, now we are ready to go to an even more complex problem, which is the human genome," she says. "So that is midterm, but even longer term, it will be very exciting to start comparing those networks."

Publications of note

In 2006, Walhout and her colleagues published "A gene-centered C. elegans protein-DNA interaction network" in Cell. The team demonstrated for the first time its approach to differential gene expression, which was in opposition to what the field had been doing up to that point. The authors postulated that highly connected transcription factors were more important for the survival of the nematode when compared to transcription factors with fewer connections, suggesting that there is a multi-layered system of gene regulation.

And the Nobel goes to ...

"I think our work is a very important contribution to the field," she says. "And that is something I would like to be recognized for by the community, even though it may not be Nobel accomplishment."

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