Genetics:
Protein Reverses Chromatin Engineering

Biological Chemistry:
Molecule Implicated in Transcription Termination

Structural Biology:
DNA Splicing Enzyme Observed in Action

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Fashions Change in Modeling Disease

Chronic Periodontitis Differs at the Microbial Level in Populations Worldwide

Brain Structure for Reward and Punishment Smaller in Cocaine Addicts

Brigham Celebrates 50th Anniversary of First Human Organ Transplant

Beth Israel Assumes Academic Oversight of Mass. Mental Health Faculty

Joslin Names Conley Chairman of the Board

Academic Officer Tapped for HMI Dubai Project

Macklis Receives Javits Neuroscience Investigator Award

Global Citizen Award Goes to Bill Moyers

HMS Family Health Guide Published in Paperback

New Appointments to Full Professor

Honors and Advances

Community Celebrates a Child's First Laugh

Front Page

Protein Reverses Chromatin Engineering

Researchers have discovered an enzyme that plays an important role in controlling which genes will be turned on or off at any given time in a cell. The novel protein helps orchestrate the patterns of gene activity that determine normal cell function. Disruption of the arrangement can lead to cancer.

Working to understand gene repression, Yang Shi (center), with Fei Lan (left), Yujiang Shi, and colleagues, discovered a new regulator of chromatin structure and gene activity, the first histone demethylase enzyme. (Photo by Jeff Cleary)

"This discovery will have a huge impact on the field of gene regulation," said Fred Winston, an HMS professor of genetics who was not involved in the work. "Shi and his colleagues discovered something that many people didn't believe existed."

The enzyme, a histone demethylase, removes methyl groups appended to histone proteins that bind DNA and help regulate gene activity. "Previously, people thought that histone methylation was stable and irreversible," said Shi. "The fact that we've identified a demethylase suggests a more dynamic process of gene regulation via methylation of histones. The idea of yin and yang is universal in biology; our results show that histone methylation is no different."

The Gene's Environment

"This discovery will have a huge impact on the field of gene regulation."

Some histone tags, particularly acetyl groups, are known to be easily added and removed, helping genes to flick on and off when needed. But the addition of methyl groups was considered a one-way process that could only be reversed by the destruction of histones and their replacement with new ones. Part of the reason scientists believed this explanation was that no one had isolated a demethylase, despite an active search.

The Shi lab was not among those in the hunt, but they stumbled onto the demethylase while probing the function of a new gene repressor protein. Postdoctoral fellow Yujiang Shi had exhausted the likely possibilities for how the mystery protein worked to suppress gene activity, so one day he tried an unlikely experiment. He had the purified protein in a test tube and decided to feed it methylated histones. His finding, that the enzyme could efficiently chew off the methyl group, leaving behind intact, unmodified histone left the postdoc Shi shaking with excitement. "Forty years ago some scientists speculated that histone demethylases existed," he said. "At first, I thought it was impossible that this protein was it." After reproducing the results using several different biochemical techniques, he began to feel comfortable that they had found the first demethylase.

Their enzyme did not remove just any methyl group from histone. Instead, it removed a very specific methyl found on lysine 4 (K4) of histone 3 (H3). H3K4 methylation is associated with active transcription, so its removal would be consistent with the gene repression function they had identified.

Evidence for Regulation

The researchers found genes similar to LSD1 in organisms from fungi to humans, suggesting that the reversible regulation of gene activity by histone methylation is fundamental to many organisms. In human cells, the demethylase is found in several gene repressor complexes. "We expect this enzyme to play a widespread and central role in establishing a repressive chromatin environment," said Yang Shi.

Now that the first demethylase has been recognized, researchers will certainly find more. "This cannot be the only demethylase," said Shi. "We know that because even at K4, this enzyme can only demethylate mono- or di-methyl histones, but tri-methyl histones are also linked to active transcription. Maybe another enzyme deals with that." And there are other lysine residues linked to either repression or activation of genes that could have their own demethylases.

Genes turning on at the wrong time or in the wrong place is a hallmark of cancer cells. In some tumors, high levels of methylation of H3K4 seem to play a role in activating genes that drive abnormal cell growth. The discovery of this H3K4 demethylase suggests a way to counterbalance this progrowth signal in some tumors. And if previous experience with histone deacetylases is any guide, the demethylases could one day be targets for cancer therapeutics.

"These findings will impact every walk of biology," said David Allis of Rockefeller University, a leader in studying the regulation and biological roles of histone tags. "Histone modifications are highly dynamic on-off switches that the cell throws a lot. These modifications affect everything DNA does, and getting the enzyme means you've got one upstream point of regulation. This will open up a wealth of new experiments."

--Pat McCaffrey