Biologists have long sought to better understand the puzzling process that turns genes on. Now, they have uncovered evidence that adds significantly to the developing picture of how genes are activated. The findings from the University of Rochester and National Institutes of Health (NIH) researchers appear in the December 27 issue of Cell.
"I feel very positive about these findings," says Alan Wolffe, a widely recognized DNA expert at NIH who was not involved in this research. "I think they're some of the most exciting in this field in the last 10 years."
The team has found the strongest evidence yet to support the widely accepted theory that gene activation is linked to the uncoiling of the tightly wound form in which DNA is usually stored.
"How genes are activated has confounded biologists for years," says C. David Allis, a professor of biology who made the finding with post-doctoral fellows Craig Mizzen and James Brownell at Rochester. "Gene activation at the right time and place is critical for cell survival and proper development. Scientists have proposed many different mechanisms for how genes are turned on. Our finding provides strong support for one of these mechanisms."
During much of its lifetime, the seven feet of DNA that resides in each of our cells exists in an inactive, tightly packed form known as chromatin. Because the DNA is wound around spool-like proteins called histones, the proteins that control DNA replication and expression cannot access the DNA to do their jobs. It's the job of enzymes known as HATs, or histone acetyltransferases, to unwind chromatin.
Now, using a unique assay developed at Rochester, Allis and his colleagues have located a new HAT that is part of a transcription complex, the group of proteins that binds to DNA and starts the process of transcribing DNA into RNA, the molecule that serves as a template for protein production. This is the first HAT discovered that has a known role in transcription.
"These findings suggest a distinct mechanism by which gene activation is occurring: The cell's transcriptional apparatus has chromatin-unfolding properties," says Mizzen. "This is the closest we've come yet to understanding how genes are activated through chromatin unfolding, and I expect that within the next two years we'll have a clearer understanding of this process."
The importance of this HAT is bolstered by its remarkable similarity among species ranging from yeast to humans, Allis says. "Such evolutionary conservation is usually the hallmark of key proteins."
The finding builds on work done in Allis' laboratory over the past year. In March, the group announced in a paper published in Cell that they had cloned and sequenced a HAT; a later paper in Nature explained how the enzyme modifies histones.
The Rochester researchers were joined by Xiang-Jiao Yang, Tetsuro Kokubo, and Yoshihiro Nakatani at the NIH. Researchers at Cambridge University in England, Penn State, and the Wistar Institute in Philadelphia also contributed.