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Are Epigeneticists Ready for Big Science?

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Science  29 Feb 2008:
Vol. 319, Issue 5867, pp. 1177
DOI: 10.1126/science.319.5867.1177

The National Institutes of Health's hefty boost of U.S. epigenomics efforts has Europe wondering where it fits in.

NIH's hefty boost of U.S. epigenomics efforts has Europe wondering where it fits in

For Peter Jones, this next week is critical. He and his colleagues at the University of Southern California in Los Angeles are putting the finishing touches on their plan to map epigenomes, the myriad of chemical modifications of human DNA and its associated proteins that influence gene activity. Jones hopes his team will become part of a newly announced $190 million, 5-year National Institutes of Health (NIH) epigenomics initiative. And he views NIH's funding as a way to jump-start an ambitious international epigenome project that he has championed since 2005. “The [international] project is huge, as huge as the Human Genome Project,” says Margaret Foti, CEO of the American Association for Cancer Research (AACR).

Yet some who study epigenetics question NIH's strategy and whether the science is ready for a large-scale international project. “Some of us biochemists think we need to know more about [epigenetic marks] before we spend all this time mapping,” says Jerry Workman, a molecular biologist at the Stowers Institute for Medical Research in Kansas City, Missouri.

Twenty years ago, most geneticists paid little mind to epigenetics. But cancer and stem cell research have gradually focused attention on these genome modifications. In a still-obscure manner, enzymes, transcription factors, and snippets of RNA converge on particular DNA sequences. They customize the expression of nearby genes, often by adding methyl, acetyl, or phosphorous groups to the DNA or the histone proteins surrounding the DNA. Methylation, for example, can silence a nearby gene and seems to be involved in some cancers. Increasingly, researchers are unearthing links between epigenetics and other diseases.

Until now, researchers have tackled epigenomics piecemeal, with different groups cataloging where on the genomes of particular cells certain epigenetic modifications occur. European researchers took the lead, for instance, setting up a Human Epigenome Consortium in 1999. In 2003, the Wellcome Trust Sanger Institute and a Berlin-based company called Epigenomics teamed up to identify the location of every methyl group bound to a human gene in an assortment of tissues (Science, 17 October 2003, p. 387). After going through three chromosomes, the project “fizzled,” says Stephen Beck of Imperial College London, who headed the Sanger effort.

Recently, faster, cheaper technologies that can better pinpoint sites of epigenetic activity have emerged, encouraging a more comprehensive attack on the epigenome (Science, 25 May 2007, p. 1120). When Jones became AACR president in 2005, he made epigenomics a priority, assembling an international task force that proposed a worldwide Alliance for the Human Epigenome and Disease. AHEAD would finally bring various epigenetics projects under one umbrella and help standardize the bioinformatics and the research. AHEAD called for a pilot phase, but no international funding materialized.

However, epigenomics has been selected as one of NIH's two new Roadmap Initiatives for 2008. By year-end, NIH plans to award $50 million to three to five epigenome mapping centers in the United States and allocate $7.5 million for a bioinformatics center. Other grants will go toward the identification of new epigenetic “marks” along the genome and new technologies for mapping them.

Mapping all epigenetic modifications is more daunting than sequencing the human genome, as there is no single epigenome. Each cell type has its own array of epigenetic marks. NIH's new initiative will likely characterize stem cells, progenitor cells, and differentiated cells from a variety of tissues. The effort “will have to make a tradeoff between how many epigenomes are analyzed and to what detail,” says Kazu Ushijima of the National Cancer Center Research Institute in Tokyo.

Those who advocate a slower approach note that so many epigenetic marks exist—in some places, there can be many on each histone—that it's difficult to know which meaningfully influence gene expression. In addition, “there's a lot of unknown modifications on histones that have not been characterized, and for all we know, they might be the most important,” says Workman. Kevin Struhl, a molecular biologist at Harvard Medical School in Boston, is also critical of the NIH initiative, arguing that more attention needs to be paid to the regulatory proteins that home in on target DNA and enable these chemical modifications. A focus on simply mapping histone modifications and DNA methylation “doesn't strike me as a good expenditure,” he says.

Turnoffs and turn-ons.

Chemical modifications of DNA or histone proteins (H), particularly their tails, affect nearby gene activity.

CREDIT: SCIENCE SIGNALING, A. M. BODE, Z. DONG, INDUCIBLE COVALENT POSTTRANSITIONAL MODIFICATION OF HISTONE H3. SCI.STKE 2005, RE4 (2005)

Nor is it clear that the NIH effort will draw in the international community. Henk Stunnenberg of Radboud University in Nijmegen, the Netherlands, complains that Europeans are being left out, as there was little time for them to team up with U.S. groups to apply for the NIH money. Even Jones admits that he's been so busy preparing his grant that his global emphasis has fallen by the wayside, temporarily. But many agree in principle that an international epigenome project is still worth pursuing. “I think it would be wonderful,” says Rolf Ohlsson, a molecular biologist at the University of Uppsala, Sweden. “It will be extremely counterproductive to do the same thing on both sides of the ocean.”

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