Scientists have discovered a “dead” gene that comes to life to tackle inflammation in the body, according to a study published in the journal eLife.
Researchers from the Stanford University School of Medicine, California, believe that this discovery could lead to new anti-inflammatory treatments without the damaging side effects of steroids.
The scientists discovered that the dead gene, which they have named Lethe, “turns off” inflammation in the body before it causes damage to healthy tissue.
Howard Chang, professor of dermatology at Stanford, says:
“Inflammation tells your body something is wrong. But after it does its job of alerting immune cells to a viral or bacterial infection or spurring them to remove debris from a wound site, it has to get turned off before it causes harm to healthy tissue.”
The researchers wanted to learn more about NF-Kappa-B. This is a complex of several proteins and “the master regulator of inflammation inside cells.” This complex also plays a role in aging.
NF-kappa-B has the ability to switch on thousands of genes in a cell’s nucleus, the researchers say. When triggered by signals at the cell’s surface, NF-kappa-B activates pro-inflammatory genes, preparing the cell to “combat viral or bacterial assaults” in response to an injury.
For the study, the scientists activated NF-kappa-B to see which genes were activated and deactivated. They say their main focus was on DNA sequences that generate long noncoding RNA molecules (lncRNAs), which remain in the nucleus and regulate genes instead of making proteins.
The researchers exposed cultured fibroblasts (found in connective tissue) from embryonic mice to TNF-alpha. TNF-alpha is an immune protein that triggers NF-kappa-B. They discovered that hundreds of lncRNAs inside the cells were moved up or down from stimulation by TNF-alpha.
The study showed that 54 of the lncRNAs discovered had been copied from “pseudogenes”. The researchers believe that these pseudogenes are copies of actual genes that have developed over evolution.
Howard Chang says:
“Pseudogenes have been considered to be completely silent, ignored by cells’ DNA-reading machinery. But we got a real surprise. When a cell is subjected to an inflammatory stress signal, it is like Night of the Living Dead.”
Prof. Chang says that different signaling or microbial components activate different groups of incRNA-encoding DNA sequences, including pseudogenes.
He adds: “They’re not really dead, after all. They just need very specific signals to set them in motion.”
Lethe was found to be one specific pseudogene activated by NF-kappa-B.
The researchers say that Lethe plays the role of vanquishing NF-kappa-B’s large influence on the genome, effectively restricting the inflammatory response in order to prevent tissue damage.
The research showed that the stimuli TNF-alpha, used to trigger NF-kappa-B, activated Lethe, but failed to activate two genes situated either side of it.
However, other stimuli turned on the other genes, but did not affect Lethe. Additionally, two other pseudogenes which closely resembled Lethe were not activated by TNF-alpha.
The researchers also found that an anti-inflammatory steroid drug called dexamethasone activates Lethe. However, other steroids that were not anti-inflammatory did not activate the gene.
Chang says:
“We’re wondering whether there might be ways to artificially raise Lethe levels without steroids. These drugs have potentially deleterious side effects such as elevated blood pressure and blood sugar, thinning of bones and general suppression of the immune system.”