Alternative Polyadenylation Orchestrates Dynamic Gene Regulation of Endogenous dsRNA

Abstract

Alu elements are the most abundant type of SINE and consist over 10% of the human genome. Inverted repeats of Alu elements (IRAlus) in 3' UTR can form intramolecular double-stranded RNAs (dsRNAs) which affect the subcellular localization and translation of the host mRNA. However, the transcriptome-wide regulatory potential of these IRAlus elements remains largely unknown. Here, we utilize dsRNA-sequencing to identify genes that contain functional IRAlus elements in 3' UTR at the transcriptome level. We find that mRNAs with proximal IRAlus elements compared to polyadenylation sites show increased nuclear retention and decreased translation efficiency while distal IRAlus-containing mRNAs are indistinguishable from those of non-IRAlus mRNAs. Moreover, our analysis of dsRNA-sequencing identifies 1019 new transcripts that may contain IRAlus elements in their 3' UTR. We further find that the gene regulation by the IRAlus element is determined by the polyadenylation factors. In particular, we show that ubiquitin-mediated proteolysis can be suppressed via lengthening of 3' UTR and subsequent inclusion of the IRAlus element. Our work unveils the dynamic regulation of IRAlus-mediated gene silencing through alternative polyadenylation sites and suggests dsRNA structure as a regulator of numerous biological processes including ubiquitination.