A tumor-suppressing protein acts as a dimmer switch to dial down gene expression. It does this by reading a chemical message attached to another protein that's tightly intertwined with DNA, a team led by scientists at The University of Texas MD Anderson Cancer Center reported at the AACR Annual Meeting 2014.

The findings, also published in the journal Nature on April 10, provide evidence in support of the "histone code" hypothesis. The theory holds that histone proteins, which combine with DNA to form chromosomes, are more intimately involved in gene expression than their general role of facilitating or hindering gene activation suggests.

The researchers found that high expression of the tumor-suppressor ZMYND11 is associated with longer survival for patients with triple-negative breast cancer.

"This study, for the first time, identifies a novel role of a histone variant protein in regulating gene transcription aside from its established roles," said senior author Xiaobing Shi, Ph.D., assistant professor of Biochemistry and Molecular Biology at The University of Texas MD Anderson Cancer Center.

"We also found that this variant, H3.3, is modified by methylation to create a specific epigenetic landscape that is accommodated by the tumor-suppressing protein ZMYND11. The protein in turn blocks gene activation," Shi said. "This is exactly the type of combined effect predicted by the histone code hypothesis."

Methylation, the attachment of a methyl group to a gene or protein, and other types of histone modifications are considered epigenetic factors, which modify a gene's behavior without changing its DNA coding.

Shi and colleagues found that the protein ZMYND11 "reads" the modified histone H3.3 by connecting to it where a tri-methyl chemical group binds to H3.3. From this position, Shi said, ZMYND11 thwarts a step in gene activation called elongation, inhibiting cancer growth.

ZMYND11 expression shrinks tumors in mice

Extensive structural analysis established that the ZMYND11- methylated H3.3 combination hunkers down in the gene's DNA.

"We knew ZMYND11 was a candidate tumor-suppressor because it's down-regulated in a number of human cancers, including breast cancer," Shi said.

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Tumor-suppressor connects with histone protein to hinder gene expression

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