The Big Ome

The Big Ome Can an international group of scientists map the entire regulatory network of a cell? In May 2004, a steady stream of more than 75 researchers from France, Italy, Singapore, and other nations around the world arrived in Ottawa, Canada, a hub of industry and government activity nestled in the confluence of three rivers. Each scientist was hand picked by Michael Rudnicki, a renowned stem-cell researcher at the Ottawa Hospital Research Institute (OHRI). For 2 days, they reported on cellular regulation and talked about transcription. At the end of the workshop, the group prepared to disperse, but before leaving, they laid the foundation for an ambitious international project aimed at understanding how the mammalian genome is regulated. They called themselves the International Regulome Consortium (IRC). In the laundry list of “omes” that have captured public attention—the genome, proteome, metabolome, and even the unknome (genes of unknown function)—the regulome is relatively new but by no means less significant. It is perhaps the largest of the undertakings, a map of the entire regulatory network of a cell. The 300-plus types of cells in the human body each express a distinct set of genes, about 10,000 of the 20,000 in our genome, which dictate its identity. Imagine the genome as a long sheet of plywood covered in 20,000 light bulbs, which alternately glow brightly or dimly depending on the fate of that cell. “We want to turn over that piece of plywood and look at all the wires and switches underneath,” says Rudnicki, CEO and scientific director of the consortium. That’s the regulome. “The task we’re facing is huge, but it’s the next step in genomics,” says Francis Stewart, a professor of genomics in the BioInnovations Center at Dresden University in Germany and member of the IRC. It’s one thing to have the code for the whole human genome; it’s another to know how that code is regulated. “The control aspects are fascinating,” says Mads Kaern, chair of systems biology at the University of Ottawa and an IRC investigator. “How and why is a single gene differentially expressed in different tissues?” asks Kaern. That information will have an important impact on stem-cell research and medicine. “Many diseases are associated with some kind of misregulation, often in gene expression,” says Richard Young, who studies transcriptional regulation at the Whitehead Institute in Cambridge, Mass., and is not involved in the consortium. “So to understand how transcription controls gene expression is of fundamental importance.” The Canadian arm of the project, based at OHRI, received $2.2 million from Genome Canada for its pilot phase, and in June 2008, the consortium signed a $4.5 million agreement with the biotech company Invitrogen to develop tools for stem-cell research. “It’s an ambitious project, but we believe we have the tools to do it in a comprehensive way,” says Rudnicki. The team plans to first identify and characterize the 1,800 transcription factors in mammalian cells. Most of the work will be done with mouse embryonic stem cells, and later with human cells. As research progresses, the team will also examine co-regulators, microRNA, and epigenetic factors like chromatin remodeling and DNA methylation. “If you want to understand how the system works, you really have to look at the whole thing,” says Ilya Shmulevich of the Institute for Systems Biology in Seattle, who is not involved in the project. It won’t be easy. The team will face many challenges, including a lack of central funding and the difficulty of isolating individual cell types. “It’s very, very hard to pull each cell type of interest out of the human body and study it,” says Young. He estimates that perhaps two dozen cell types can be extracted from the body with adequate purity, “but even that will be a struggle.” Still, he believes that the IRC is up to the challenge. “I think the group of people [Rudnicki] put together are excellent,” he says. Imagine the genome as a long sheet of plywood covered in 20,000 light bulbs, which alternately glow brightly or dimly depending on the fate of that cell. “We want to turn over that piece of plywood and look at all the wires and switches underneath,” says Michael Rudnicki. The project has already hit rough spots. In the spring of 2009, following the worldwide financial crisis, Genome Canada pulled its funding, an expected $17 million. In Ottawa, the project was downsized. “We were scrambling a bit, but we tried to maintain our progress,” says Kaern. The loss of funding has yet to affect the IRC’s European community, says Stewart, “but it’s terribly disappointing.” Still, thanks to $3.6 million from the Ontario Research Fund and past funding from the Canada Foundation for Innovation, “the project is very much alive and moving forward,” says Rudnicki. “We are not as much in the driver seat as we were before, but we are able to put our heads down and look to the work.” Currently, the Ottawa team is both the secretariat and repository for the IRC. “The overall goal is to bring all the data together,” says Stewart. “We’ll need to do that before we can understand how regulation works.” At the University of Ottawa, Kaern is developing databases to analyze and order incoming data. “That’s going to be the key—to figure out clever ways of integrating these data sets to learn how the system works,” says Shmulevich. Kaern is also developing software to simulate regulation pathways, so researchers can model a system on the computer, then test their predictions in a wet lab. Rudnicki hopes they will soon be prepared to accept international data. Across the Atlantic, Stewart and his team in Dresden are concentrating on technologies to speed up the analysis of transcription factors. Instead of using classical biochemistry to elucidate the structure and function of transcription factor protein complexes and DNA binding sites, Stewart is applying a technique called recombineering, which involves tagging transcription factors in the cell and then pulling them out with other associated proteins or genes attached. Using the technique, regulatory interactions can be mapped in high throughput, says Stewart. It’s only by working together that scientists will be able to map the entire mammalian regulome. “The scale of the project is simply too immense for any single lab, university, province, or country to do it alone,” says Kaern. Participating Countries: Canada France Singapore Australia Netherlands United Kingdom United States

The Big Ome

The Big Ome

Can an international group of scientists map the entire regulatory network of a cell?

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Megan Scudellari

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December 2010

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