Odd Couple: Two mechanisms for gene silencing unexpectedly team up (Gene regulation; Silencing)
Authors: Leslie Mitch 
Published: August 2003

If flipping off the light in the bedroom turns off the refrigerator, it's time to call the electrician. But the switches that control our genes might work this way. New research reveals that one method for shutting down DNA triggers another, adding a twist to the notion that the packaging of DNA determines its activity.

The DNA in our cells comes wrapped around histones, globular proteins with dangling tails. Teams of eight histones huddle together to form a spool, and the tails protrude from this bundle. By affixing a methyl or acetyl group to the tail of a histone, a cell can shut off--or silence--a gene or a block of genes. Faulty silencing can spark cancer and drives aging in yeast and possibly in other organisms (see
Kaeberlein Perspective
). Cells also adorn histone tails with ubiquitin, a small protein known for its ability to target other proteins for destruction. Two years ago, molecular biologist Mary Ann Osley of the University of New Mexico in Albuquerque and colleagues showed that an enzyme called Rad6 added ubiquitin to the tail of H2B, one of the four types of histones. Other researchers demonstrated that eliminating the enzyme undermined gene silencing.

Zu-Wen Sun and C. David Allis tie these observations together. The researchers had previously shown that when another kind of histone, H3, picks up a methyl group, certain genes turn off. In their new work, Sun and Allis found that H3 histones in yeast cells lacking Rad6 carry no methyl groups, suggesting that the enzyme was necessary for pasting on the silencing tags. Further experiments indicated that the enzyme acts indirectly. The team created a mutated version of the H2B histone that couldn't attach to ubiquitin. Yeast cells with this altered histone showed no methylation on their H3 histones. The results imply a chain reaction in which the addition of ubiquitin to H2B histones somehow induces the methylation of H3 histones, which then leads to gene silencing, says Allis, a biochemist at the University of Virginia, Charlottesville.

Osley says that the study extends the histone code hypothesis, the idea that the combination of methyl groups and other tags on histones dictates whether DNA scrunches up or relaxes, allowing access by enzymes that copy DNA, allow it to swap segments with other DNA molecules, and make RNA. The work shows that changes to one histone are transmitted to others, says Osley. How the addition of ubiquitin to one histone promotes methylation on a different--and sometimes distant--histone remains an enigma, says Allis. However, ubiquitin is nearly as large as a histone, and it might use brute force. "It may be like a crowbar that causes the chromatin to open up and allow methylating enzymes to get on board," says Allis. Another possibility, says biochemist Jerry Workman of Pennsylvania State University, University Park, is that ubiquitin might serve as a docking station for methyl-adding enzymes, which then would work on another histone in the bunch. Whatever the mechanism, says Workman, the paper suggests that it "is going to be even more complicated and exciting than we thought."

--Mitch Leslie

Z.-W. Sun and C. D. Allis, Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast.
Nature
, 23 June 2002 [e-pub ahead of print].
[Abstract/Full Text]