A Thread in the Genetic Zipper

rm_rat_fawn1_0006_lresIn the first part of his “The Genome at 10” series on Sunday, Nicholas Wade of the New York Times wrote about frustration in the wake of the Human Genome Project. Despite optimistic promises at its unveiling in 2000, scientists haven’t found as many of the answers to disease in DNA as was initially hoped. Instead, our knowledge of the genome has created even more questions and complexity in the search for the genetic sources of disease.

As a result, more and more attention has been paid in recent years to epigenetics, the non-genetic control of gene expression. Through processes such as DNA methylation and histone acetylation, biology has developed ways of controlling the volume of protein production – silencing or activating a particular gene when its protein is needed.

“Picture the reading of DNA (gene transcription) as the opening of a zipper,” described Stephen Archer, chair of cardiology at the University of Chicago Medical Center. “Transcription factors must run along this DNA zipper to allow the DNA to open so the gene can be read. Methylation blocks this reading, much like having a thread stuck in the zipper prevents its opening. This way, methylation silences a perfectly normal gene.”

For a disease such as pulmonary arterial hypertension (PAH), which Archer studies, the search for a straight genetic cause has been unsatisfactory. PAH is marked by blockage of blood vessels to the lungs, and is known to run in families. 10 years ago, when a PAH-linked genetic mutation was found in a gene called BMPR2, researchers hoped that aberrant genetics were to blame for the disease. But at most, only a quarter of people with that mutation developed PAH, and not all people with PAH carried that mutation, Archer said. That led PAH researchers  to look elsewhere for answers, including at a mitochondrial protein called superoxide dismutase 2 (SOD2), which is known to be lower in PAH patients.

But when researchers looked at the SOD2 gene in people with PAH, they found no mutation. That suggested epigenetics may be to blame, Archer said.

“The question was why is SOD2 downregulated?,” Archer said. “So we began looking at the possibility it might be present but functionally inhibited.”

Those experiments, published last week in the journal Circulation, were easier thanks to a rat strain with a naturally-occurring case of PAH called fawn-hooded rats. Known for their distinctive coloring, the rats also offered a useful model for studying SOD2 deficiency and its role in PAH.

“It was recognized early on that these rats were very sensitive to changes in oxygen levels, so they would get severe PAH apparently spontaneously. It’s one of the few animals that develops a disease without us giving it a drug,” Archer said. “If the oxygen level was normal the fawn-hooded rat reads it as if it was hypoxic, so it was triggering all these responses you would normally see at high altitude.”

Experiments confirmed that SOD2 is also lower in the fawn-hooded rats, and that the gene for SOD2 was unchanged, but silenced via hypermethylation. Demethylating the gene or replacing SOD2 in the rats improved their PAH-like symptoms, as measured by running time on a treadmill (the same test used in humans).

“That’s an exciting aspect of epigenetics,” Archer said. “Unlike a mutation that might be hard to fix, if a gene were silenced by methylation and you wanted to turn it back on there are drugs that do that, and you might be able to reactivate it.”

Both of those treatments would not be immediately practical in humans. But the discovery of a direct link between methylation of SOD2 and PAH symptoms opens a path to possible new diagnostics and treatments for the disease. That brings cardiovascular disease in line with cancer as areas where epigenetic changes are the new suspects on the radar. Intriguingly, another group recently found a relationship between epigenetic silencing of the SOD2 gene and certain types of cancer, suggesting both diseases may share a common mechanism.

“This introduces a new concept: DNA methylation, a form of epigenetics, may play a role in pulmonary arterial hypertension,” said Jalees Rehman, MD, Assistant Professor of Medicine and another author on the paper. “We think this is going to be a big part of cardiovascular research in the next decade to come.”

About Rob Mitchum (526 Articles)
Rob Mitchum is communications manager at the Computation Institute, a joint initiative between The University of Chicago and Argonne National Laboratory.
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