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Fruit Fly Study Hints at RNA Editing Effect on Transposon-related Gene Silencing

NEW YORK (GenomeWeb News) – Researchers at Brown University and the St. Laurent Institute have found ties between RNA editing and transposon-related gene silencing in fruit flies — findings that they suspect may extend to other organisms.

In a study appearing online today in Nature Communications, the team used protein localization, gene deletion, expression profiling, and other approaches to tease apart interactions between transposon-associated double-stranded RNA and components of an RNA editing system in Drosophila.

Results of the analysis indicated that double-stranded RNA editing by an enzyme called ADAR can loosen the reins on an RNA interference pathway that typically silences so-called Hoppel transposons with the help of tightly packaged repressive heterochromatin.

In the absence of ADAR, investigators saw shifts in fly lifespan in some experiments and reporter gene expression shifts in others, underscoring the enzyme's apparently antagonistic interactions with transposon-related silencing systems.

"What ADAR does is fine tune this regulatory network," first author Yiannis Savva said in a statement. "In cells where you have ADAR, the network is activated. In cells where you don't, it's silenced. It provides dynamicity."

Savva was a graduate student in senior author Robert Reenan's Brown University molecular biology, cell biology, and biochemistry lab when the study began. He is currently a post-doctoral researcher at Brown.

Though the current study was performed in fruit flies, members of the team noted that RNA editing components could conceivably make transposon-related contributions to gene expression variation in other organisms as well.

"ADAR in humans functions the same way it does in flies, and double-stranded RNAs are made in humans the same way," Reenan said in a statement. "They are all generic, off-the-shelf staples of the biological toolkit. This is not anything that is particular to flies."

Transposable elements are well known for hopping around host genomes, sometimes producing pronounced changes to parts of the genome where they land. Host cells can use a range of responses to minimize transposon-induce damage, the researchers noted, from dicing up double-stranded RNA to keeping transposon sequences tightly wound around chromatin proteins.

"Repressive heterochromatin is established through the RNA interference pathway, triggered by double-stranded RNAs that can be modified via RNA editing," Savva, Reenan, and co-authors wrote. "However, the biological consequences of such modifications remain enigmatic."

To explore this system in more detail, the group started by performing localization experiments in salivary gland samples from Drosophila larvae.

In the process, the team uncovered physical interactions between the ADAR protein and double-stranded RNA on chromosome 4, which it subsequently attributed to the presence of transposable elements from the Hoppel family.

As they delved into this relationship further, the researchers saw clues that the RNA editing enzyme was diminishing the effectiveness of RNA interference and silencing of Hoppel transposon-associated sequences.

For instance, the team detected a dip in reporter gene silencing in fruit fly cells with higher levels of the ADAR enzyme, whereas such silencing remained relatively strong in cells with lower ADAR levels.

Such effects appear to stem from a decline in heterochromatic silencing of transposons via RNA interference pathways in the presence of the RNA editing ADAR enzyme, researchers reported. In follow-up experiments, they found that fruit flies with unusually low ADAR levels tended to live longer than counterparts with typical levels of the enzyme.

And by dialing ADAR activity up or down in fruit flies with Hoppel tranposon repeats near an eye color reporter gene, meanwhile, the group determined that they could influence the range of resulting eye colors in the flies.

Individuals with a good deal of the enzyme were more apt to have red eyes, reflecting reduced silencing of those eye color-related sequences. On the other hand, flies with little ADAR more often had white eyes, consistent with efficient gene repression in the region.

"Our results explicitly demonstrate a functional intersection between the processes of RNA editing and RNA silencing," the study authors wrote.

"The implications of our results, given the universal prevalence of [double-stranded RNAs] as components of transcriptomes, are that ADAR activity has an evolved role in determining the fate of RNAs entering silencing pathways," they concluded, "thus globally influencing somatic genomic integrity, gene expression, and downstream organismal phenotypes."