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Novel enzyme offers new look at gene regulation

Scientists at the University of North Carolina at Chapel Hill have purified a novel protein and have shown it can alter gene activity by reversing a molecular modification previously thought permanent.

In the study, the authors showed that a protein called JHDM1A is able to remove a methyl group from histone H3, one of four histone proteins bound to all genes. Until just last year, the addition of a methyl group to a histone had been regarded as irreversible.

"That histones can become methylated has been known for over three decades, and just now we're learning that those methyl groups can also be removed," said Dr. Yi Zhang, the lead author.

Zhang is professor of biochemistry and biophysics at UNC's School of Medicine and the university's first Howard Hughes Medical Institute investigator. He also is a member of the UNC Lineberger Comprehensive Cancer Center.

The new study is now online in the journal Nature.

"Human genes are so tightly compact within the nucleus that if the DNA of a single cell were unwound and stretched, it would be a line of about two meters in length," said Zhang. "Histones are necessary to package the DNA so that it fits inside a cell's nucleus."

Because they are so intimately associated with DNA, even slight chemical alterations of histones can have profound effects on nearby genes. Depending on the precise location and how many methyl groups are added, their presence can either switch affected genes on or off.

The first enzyme to remove methyl groups from histones, or histone demethylase, was identified last year. This was a breakthrough in the study of histone modifications, but Zhang thought pieces of the puzzle were still missing.

"We hypothesized that there were more demethylase enzymes out there for two reasons," Zhang said. "For one, the previous demethylase identified, called LSD1, could not remove a chain of three methyl groups from a histone, or a trimethyl group. Secon
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Source:University of North Carolina School of Medicine


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