Gene regulators bind promiscuously, but often do nothing

February 12, 2008

Biologists are developing ever more sophisticated means to characterize molecular interactions in living systems. But a new study suggests that many of the interactions detected by a widely-used experimental method are functionally irrelevant.

ChIP-chip is a “hot technique” in biology, allowing scientists to visualize the binding between regulatory proteins and genes and thereby investigate the mechanisms and controls that operate as an organism develops from a fertilized egg to a complicated adult. However, a new study published in this week’s PLoS Biology shows that there are many more of these binding events than expected and that most of them appear not to be involved in gene expression.

The fruit fly is an important model for the study of development, the process by which embryonic cells are able to multiply and form three-dimensional structures that eventually become tissues, organs and finally entire organisms. The blueprints for this transformation are encoded in the genes of every cell, and are “read out” by vast networks of regulatory proteins called transcription factors, which determine where and when genes are expressed.

It has been generally assumed that transcription factors are targeted to a limited set of genes and that they regulate expression wherever they are bound. However, a team of researchers from the Lawrence Berkeley National Lab and the University of California at Berkeley, led by Mark Biggin and Michael Eisen, found that there are thousands of regions reproducibly bound by each factor. “This is several orders of magnitude more genes than these factors are thought to regulate,” said Eisen, “raising the question of what the function of the binding is.”

Rather than simply classify regions as bound or unbound, as other researchers have done, the Berkeley team examined the full scope of binding observed in their ChIP-chip data and focused on differences in the amount of factor bound to each gene. They found a clear relationship between the number of factor molecules bound at a given site, and the site’s role in gene regulation; DNA sites that bound the most molecules were those already thought to be key to the regulation during development. Much of the low level binding detected at thousands of genes, while clearly representing real molecular interactions, appears to play no role in regulating gene expression.

Based on their observations, the Berkeley Lab researchers argue that many of the regulatory connections proposed in earlier studies are likely to be incorrect. “Realizing that much of the binding detected in these assays may be non-functional significantly impacts how the results of these experiments should be interpreted,” said Biggin. “The analysis and conclusions of published ChIP-chip studies should be reexamined with this possibility in mind.”

Citation: Li X, MacArthur S, Bourgon R, Nix D, Pollard DA, et al. (2008) Transcription factors bind thousands of active and inactive regions in the Drosophila blastoderm. PLoS Biol 6(2): e27. doi:10.1371/journal.pbio.0060027

Source: Public Library of Science