August 26, 2010

Study details on/off switch for gene expression

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From left, Zu-Wen Sun, Ph.D., Mahesh Chandrasekharan, Fu Huang and colleagues are studying how cells regulate gene expression. (photo by John Russell)

Study details on/off switch for gene expression

Turning the right genes “on” and “off” at the right times is critical for proper cell function. Faulty regulation of gene expression can contribute to cancer development.

“If we can understand how genes are tightly regulated, then we might be able to target irregular gene expression for cancer treatment,” said Zu-Wen Sun, Ph.D., assistant professor of Biochemistry and a member of the Vanderbilt-Ingram Cancer Center.

Sun's group is exploring how cells regulate gene expression, using the budding yeast Saccharomyces cerevisiae as a model system.

One way that cells flip the switches of gene expression is by modifying histone proteins — DNA wraps around groups of these proteins in the cell nucleus. Chemical modifications (“marks”) on the histones signal whether nearby genes should be turned on or off.

Sun and his colleagues have now detailed the activity of a histone-modifying protein called Jhd2. Jhd2 — a yeast protein that is similar to the human protein SMCX — removes chemical “marks” from a particular histone. A mutation in SMCX has been linked to mental retardation, and in collaboration with the group of Scott Hiebert, Ph.D., professor of Biochemistry, the researchers showed that the mutation affects the protein's stability.

The team's paper in the Aug. 6 issue of the Journal of Biological Chemistry was selected as a “Paper of the Week.” This distinction is awarded by the editors to the top 1 percent of papers published each year in the journal.

“Our work gives details about Jhd2's mechanism and how it's regulated — very basic results — and it also has an implication for human disease,” Sun said. “It begins to explain how a particular mutation in this enzyme can cause mental retardation.”

Sun and his colleagues demonstrated that two regions of the Jhd2 protein interact with each other, and that disruption of this interaction — for example by mutations like the one in SMCX — causes the protein to become unstable.

The investigators discovered that another protein monitors the interaction of the two domains in Jhd2, and targets Jhd2 for degradation if the domains do not interact correctly. Their findings also suggest that this monitoring mechanism is conserved between yeast Jhd2 and human SMCX.

It might be possible, Sun said, to develop drugs that can stabilize the interaction and restore the protein's function, which could help patients with mental retardation or other diseases caused by mutations in Jhd2-like proteins.

“The potential for helping patients is a long way off, but the more we know, the more likely it will be that we can discover a way to correct the problem.”

The team also probed how Jhd2 binds to the DNA-histone complex known as chromatin. They showed that a part of the Jhd2 protein called the “PHD finger” — a domain that is evolutionarily conserved from yeast to humans — was required for Jhd2 to interact with chromatin. However, it did not bind to the histone site that PHD finger domains in other proteins normally recognize.

Sun and his colleagues are now trying to identify the PHD finger-binding site on histone, which could represent a drug target site for regulating Jhd2/SMCX activity.

Graduate student Fu Huang was the first author of the paper. The National Institutes of Health, Vanderbilt-Ingram Cancer Center and Robert J. and Helen C. Kleberg Foundation supported the research.