Nitric oxide can regulate gene expression

Douglas Thomas, associate professor of medicinal chemistry and pharmacognosy at UIC, and co-workers discovered that nitric oxide plays an important role in epigenetics -- heritable alterations in gene expression caused by mechanisms other than changes in DNA sequence.

One such example, Thomas said, are modifications of specialized proteins called histones, which are responsible for packaging DNA in the cell nucleus and influencing how genes are regulated.

Genes wound very tightly around their histones are not expressed as strongly as genes that are more loosely wrapped. The latter are more easily accessible to the cellular machinery that translates genes into their protein products.

"Small alterations on these histones act as a molecular switch to turn certain genes on and others off," Thomas said. "It's no surprise then that abnormal histone modifications have been associated with a tremendous variety of diseases."

Attaching chemical bits called methyl groups at certain histone sites can shut down genes that are vital for suppressing tumor formation, or activate genes that cause cancer, Thomas said. In addition, alterations in the expression of enzymes that change the methylation of histones have been linked to disease and poor survival in a variety of conditions.

In a new study published in the Journal of Biological Chemistry, Thomas and his colleagues focused on the protein KDM3A, which removes methyl groups from histones. The group discovered that nitric oxide could inhibit the ability of the protein to remove histone methyl groups.

"We also found that nitric oxide can differentially regulate the expression of a variety of histone methyl-modifying enzymes, many of which have strong associations with specific cancers," Thomas said.

This is the first study to demonstrate an epigenetic model of nitric oxide signaling that has the potential to "change our fundamental understanding of both nitric oxide biology and epigenetic regulation," Thomas said.

"This could significantly alter our understanding of gene expression in health and disease."

Co-authors on the report are Jason Hickok, a visiting research assistant professor at UIC, and graduate student Divya Vasudevan. The work was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number R01GM085232.