A deeper look at gene control

CAMBRIDGE, Mass. (August 17, 2006) — Don’t be fooled by those neat and orderly textbook illustrations of the inside of a cell. Cellular activity resembles Grand Central Station at rush hour far more than it resembles a game of croquet. Countless proteins and organelles are squeezed together, pitching signals back and forth and back again, carrying out tens of thousands of simultaneous functions.

The control center for all this hustle and bustle is the genome, which stores the operating instructions and responds to extracellular events. It receives its intelligence about the outside world via signal transduction pathways—designated routes by which long lines of proteins pass on a piece of chemical information from the cell surface all the way into the nucleus, bucket-brigade style.

While researchers have gotten pretty good at understanding these pathways, they get stumped at the last few steps, at the precise moment that this pathway concludes in the expression of a particular gene. This is because while evolution has conserved signal transduction pathways throughout many species, it has not conserved the specific gene that the pathway targets. If pathway A in the fruit fly leads to gene B, that same pathway in the mouse may instead lead to gene D. This knowledge gap poses a significant problem, because understanding exactly how specific pathways activate particular genes is essential for drug development.

In a recent paper published in Science, scientists in the lab of Whitehead Member Richard Young, led by postdocs Dmitry Pokholok and Julia Zeitlinger, report that a well-known class of proteins called kinases may fill in the dotted lines that connect signal transduction pathways to the genes they regulate.

Kinases are enzymes, proteins whose main function is to catalyze a reaction in other proteins. In particular, kinases target transcription factors, proteins that switch genes on and off. Researchers know that most (though not all) kinases reside in the cell’s nucleus. But they have never paid much attention to the kinases’ exact locations, reasoning that if a kinase is technically able to activate a transcription factor from any place in the cell, its precise location is probably not important.

Using microarrays to analyze the whole genomes of yeast cells, Pokholok and Zeitlinger decided to track down the location of kinases that reside in the nucleus. The results were surprising.

“Many kinases we studied were physically associated with the genome and some of them were located right on the gene itself,” says Zeitlinger. “This surprised us because most molecules associated with gene regulation bind to regions just outside the gene. Here, however, the kinases were located directly on the protein-coding regions of the genes. We never expected that.”

This surprise was pleasant because, unlike other molecules involved in gene expression, kinases are relatively easy to connect back to the signal transduction pathways.

“This might just turn out to be invaluable for understanding how these cellular pathways relate to gene expression,” says Zeitlinger.

The next step, adds Pokholok, is to confirm these findings in higher organisms.

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Richard Young’s primary affiliation is with Whitehead Institute of Biomedical Research, where his laboratory is located and all his research conducted. He also is a professor of biology at Massachusetts Institute of Technology.
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Pokholok, D. K., Zeitlinger, J., et al. (2006). Activated signal transduction kinases frequently occupy target genes. Science,  313(5786), 533-6. doi:10.1126/science.1127677