Researchers from Sylvester Comprehensive Cancer Center, the John P. Hussman Institute for Human Genomics and The Miami Project to Cure Paralysis at the University of Miami Miller School of Medicine, in collaboration with colleagues from other institutions, have discovered a direct link between G protein-coupled receptors (GPCRs) and DNA demethylation — an important finding that could be implicated in human health and diseases.
“Our DNA directs cells to produce proteins, and these proteins ultimately determine our genetic traits,” said one of the lead researchers, Gaofeng Wang, Ph.D., a member of Sylvester and associate professor of human genetics and ophthalmology. “When the environment changes, our cells must rapidly respond by altering our gene response. However, it remains largely unclear how the cell coordinates dynamic epigenetic changes in response to an ever-changing environment.”
DNA demethylation is a mechanism used by cells to control how our genes express themselves. A lack of control over our gene expression can lead to cancer and other diseases. DNA demethylation occurs when methyl groups are removed from our DNA, which is initiated by a chemical reaction that is catalyzed by TET enzymes. Without iron, this reaction would not happen because iron is an essential cofactor for TETs.
In the researchers’ study, evidence was found that cAMP, the second messenger of GPCRs, increases the iron pool within the cell and subsequently promotes DNA demethylation. These findings suggest that GPCR signaling can promote DNA demethylation and drastically influence how our cells respond to the environment.
“Agents that directly affect cAMP production in the cell can also significantly influence this process,” said Wang. “For instance, caffeine, which is regularly found in popular beverages such as coffee, tea, and soft drinks, as well as bicarbonate (baking soda), can elevate cAMP and enhance DNA demethylation. Essentially, environmental influences, such as a cup of coffee, can directly affect the way our genes choose to express themselves.
“This discovery is especially important news for pregnant women because these processes are most active during embryonic development and can have a powerful influence on genes in infants.”
Additionally, approximately 50 percent of all current drugs on the market are targeting GPCRs. These drugs should be carefully evaluated for long-term usage, as their impact on DNA demethylation should not be overlooked.
The study, “cAMP Signaling Regulates DNA hydroxymethylation by Augmenting the Intracellular Labile Ferrous Iron Pool,” was published online by eLIFE with Wang as corresponding author.
Additional Miller School authors include Wang’s postdoctoral fellow, Vladimir Camarena, Ph.D., as first author, Paula V. Monje Ph.D., research assistant professor of neurological surgery and the Miami Project, postdoctoral associate Sushmita Mustafi, Ph.D., and graduate students David Sant and Tyler Huff. Collaborators include Adam Renslo, Ph.D., from the University of San Francisco and Christopher Chang, Ph.D., from the University of California-Berkeley and Howard Hughes Medical Institute.
This work was mainly supported by grants from the National Institute of Neurological Disorders and Stroke (R01NS089525) and the National Cancer Institute (R21CA191668).
Miller School of Medicine