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Night of the living dead gene: Pseudogene wakes up, puts chill on inflammation

night of the living deadBecause proteins do the vast bulk of visible work inside every living cell, scientific efforts to understand the workings of the genome (the sum of all the DNA in all the chromosomes of each of our cells) have traditionally focused on genes - the recipes for proteins.

But only one-fiftieth of the vast stretches of DNA that constitute our chromosomes consists of protein-coding genes. The rest of it was long looked at as little more than a junkyard composed of vast expanses of genetic gibberish.

There’s been a sea-change in scientific perceptions of “junk DNA." In recent years the applicable metaphor has been less a junkyard than a graveyard, littered with broken skeletons of, for example, viruses and other creepy-crawlies that had curled up in the genome and gone to sleep forever.

Scattered among that detritus are a large number of pseudogenes. These are DNA sequences that closely resemble genes but don’t code for proteins. There are more than 11,000 in the human genome - that's about one for every two bona fide protein-coding genes. Scientists figure pseudogenes are extra copies of working genes that were accidentally inserted into the genome during divisions of our ancient ancestors' germ cells. Redundant but harmless, these DNA doppelgangers were permitted by evolution to come along for the ride. Over the intervening eons, pseudogenes have gradually piled up, mutated and decayed to the point where, it's thought, they no longer do anything at all.

It turns out that although they don't generate proteins, pseudogenes can generate RNA, which intrigues Stanford molecular biologist Howard Chang, MD, PhD. RNA is best known as the intermediate material in classic protein production. Gene-reading machines in cells produce RNA copies, or "transcripts," of protein-coding genes. These RNA transcripts leave the cell nucleus and head for the cytoplasm, where they transmit genes’ instructions to protein-making machines situated there.

Chang and other researchers (including 1989 Nobel Prize winner Tom Cech, PhD, of Colorado University, and 2006 Nobelist Andy Fire, PhD, of Stanford) have rocked the field by showing that RNA does much more than just help make proteins.

In a study just published in eLife, Chang and his colleagues have identified a pseudogene that, aroused by an intracellular alarm responsible for fanning inflammation's fires, generates a "long, noncoding RNA" (a species of RNA whose discovery Chang  pioneered and I wrote about at length in this Stanford Medicine article) that shuts off the alarm - a classic case of what engineers and biologists call negative feedback. As Chang told me when I interviewed him for my news release on this study:

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.

That's what the cell-soothing pseudogene does. Chang’s team has named it Lethe, after the stream in Greek mythology that makes the deceased who cross it forget their pasts.

Previously: New job description for RNA, oldest professional biomolecule, Master regulator for skin development identified by Stanford researchers and The RNA insurrection: Genes' "humble servant" rules from behind the scenes
Photo by techno.donm

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