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Edited RNA + invasive DNA add individuality
In a new paper published in Nature Communications, scientists reveal how an enzyme called ADAR, edits double-stranded RNAs in humans, flies, and many other creatures, by loosening the system that keeps “Hoppel” transposons silenced in fruit flies. Transposons are silenced by being tightly wound around tiny balls of material called chromatin. ADAR loosens the tightly wound RNA of the "silenced" Hoppel transposons in fruit flies — allowing the gene to become active.
As the amount of ADAR varies from one individual to another, the amount of jailbreaking from chromatin prisons varies too. After realizing an abundance of ADAR reduces silencing in flies — and a lack of ADAR means widespread silencing — the researchers measured two levels of ADAR activity: in life span and in eye color.
The study was focused on fruit flies, ADAR, and the double-stranded RNA of the Hoppel transposon, but the ability of RNA editors to loosen the silencing of at least some transposons may be a source of individual variation in humans and other species too, said Brown University biologist Robert Reenan, senior author of the new study published online. Editing of double-stranded RNA — or a lack of editing — has already been linked to diseases in people, including amyloid lateral sclerosis and, specifically in the case of ADAR, Aicardi-Goutières syndrome.
Many of Reenan’s studies focus on ADAR’s editing activity in the development of the nervous system, this investigation began years ago when lead author and then graduate student Yiannis Savva happened to overexpress ADAR in fruit fly salivary gland cells and found some ADAR bound to an unexpected site on chromosome four.
Reenan recalled: “I told him that’s either an artifact or it will be the centerpiece of your thesis.”
Various tests revealed that the chromosome four site was home to several Hoppel transposons and double-stranded RNA.
Savva and Reenan were curious about what business ADAR had with the transposon. Through years of experiments, they moved the transposons to gene locations where they normally weren’t found — and always subsequently found ADAR. Deleting the double-stranded RNA from chromosome four caused ADAR to disappear.
Savva and his collaborators then measured silencing of tranposons with varying levels of ADAR and found that the more ADAR there was, the less silencing of genes there was.
In collaboration with Stephen Helfand, an expert on the biology of aging, the team found that a reduction of ADAR increased fruitfly life span.
“As a loss of [gene] silencing has been associated with aging in Drosophila and other organisms, we performed lifespan analyses on [low-ADAR] adults and wild-type controls and found a ~20-percent increase in the median life span of [low-ADAR] males and females,” the authors wrote in Nature Communications.
Later they looked at eye color, using natural (wild-type) flies and those where ADAR activity was either artificially curtailed or excessively active. Natural or wild-type flies have eyes that run from red to white with various blends in between, reflecting the amount of silencing of their eye color gene. In flies with excessive ADAR, there was little gene silencing and eyes were red much more frequently. In the ADAR-hamstrung flies, virtually all of the eyes were white (reflecting a lot of silencing of the red color gene).
Ultimately, Savva said, ADAR appears to be allowing transposons like Hoppel to exercise their capacity to regulate gene expression, even though they are really just uninvited guests in the genome.
Said Savva:“What ADAR does is fine tune this regulatory network. In cells where you have ADAR, the network is activated. In cells where you don’t it’s silenced. It provides dynamic control.”
In other words, some of the differences among us may be apparent in the eyes of flies.
In addition to Savva, Reenan, and Helfand, authors on the paper are James Jepson, Yoah-Jen Chang, Rachel Whitaker, Brian Jones, Nian Jiang, and Guyu Du of Brown; Georges St. Laurent of Brown and the St. Laurent Institute; and Michael Tackett and Phillipp Kapranov of the St. Laurent Institute.
The National Institute on Aging (grants: AG16667, AG24353, AG25277) and the Ellison Medial Foundation funded the research.
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Original press release:http://news.brown.edu/pressreleases/2013/11/eyes