RNA editing regulates transposon-mediated heterochromatic gene silencing

Abstract

Heterochromatin formation drives epigenetic mechanisms associated with silenced gene expression. Repressive heterochromatin is established through the RNA interference pathway, triggered by double-stranded RNAs that can be modified via RNA editing. However, the biological consequences of such modifications remain enigmatic. Here we show that RNA editing regulates heterochromatic gene silencing in Drosophila. We utilize the binding activity of an RNA editing enzyme to visualize the in vivo production of a long double-stranded RNA trigger mediated by Hoppel transposable elements. Using homologous recombination, we delete this trigger, dramatically altering heterochromatic gene silencing and chromatin architecture. Furthermore, we show that the trigger RNA is edited, serves as a key regulator of chromatin state, and that dADAR auto-editing generates a natural suppressor of gene silencing. Lastly, systemic differences in RNA editing activity generates inter-individual variation in silencing state within a population. Our data reveal a global role for RNA editing in regulating gene expression.

Chromatin-modifying genetic interventions suppress age-associated transposable element activation and extend life span in Drosophila

“…4C), using the conditional inducible GeneSwitch system, was able to extend life span, with flies fed the gene-activating drug RU486 outliving a genetically identical control cohort fed only the diluent control EtOH. Together with previously published data (21,25), these observed life span extensions suggest a coordinated response integrating maintenance of heterochromatin structure, TE suppression, and longevity.…”

“…In addition to their effects of delaying age-related heterochromatin gene and TE silencing loss, both increased Sir2 expression and decreased Adar expression have been shown to extend life span in flies (21,25), whereas Dicer-2 and Ago2 mutants are short-lived (15,24). Given our findings presented earlier, we examined whether increased expression of Su(var)3-9 or Dicer-2 also have a positive effect on life span.…”

“…Sir2 has a central role in aging, with increased gene dosage shown to extend life span in yeast (2) and in nine of 10 studies in nematodes and flies (25)(26)(27)(28). Hypomorphs of Adar, a negative regulator of the siRNA pathway, also exhibit an extension of life span (21). These pathways share an ability to affect heterochromatin formation and life span.…”

Genome-wide profiling of the C. elegans dsRNAome

“…In support of this idea, small RNAs, which in some cases might derive from EERs, mediate homology-driven deposition of heterochromatin in C. elegans (Ashe et al 2012;Buckley et al 2012;Gu et al 2012). In Drosophila, ADAR antagonizes heterochromatin deposition over transposable elements (Savva et al 2013). ADAR antagonizes other dsRNA-mediated pathways, such as miRNA and siRNA biogenesis (Yang et al 2005;Heale et al 2009a,b;Vesely et al 2012;Warf et al 2012), and in a similar way, editing of C. elegans dsRNAs, or simply dsRNA binding, could regulate small RNA-mediated chromatin remodeling.…”

A-to-I editing of coding and non-coding RNAs by ADARs

“…It was proposed that dAdar edits a long dsRNA generated from Hoppel loci, thereby preventing Dicer from processing it into endo-siRNAs, which are required for RNAi-mediated hetero chromatin formation and gene silencing 109 . However, the involvement of Dicer in this transposon-silencing mechanism and the generation of endo-siRNAs from Hoppel elements remain to be shown.…”