Context-specific effects of sequence elements on subcellular localization of linear and circular RNAs

Long RNAs, including mRNAs and long noncoding RNAs (lncRNAs) vary extensively in their post-transcriptional fates, and this variation is attributed in part to short sequence elements that drive RNA localization and stability, typically through interactions with RNA binding proteins (RBPs).Productive RNA processing, including splicing, has been associated with efficient RNA export. Splicing also gives rise to circular RNA products, stable RNA molecules that lack features traditionally associated with efficient nuclear export, such as a 5prime cap. Here, we use massively parallel RNA assays to study how short sequences derived from lncRNAs or circRNA influence the subcellular localization and stability of linear and circular spliced RNAs, and of RNAs that are not spliced. We find that the effects of sequence elements strongly depend on the host RNA context, with limited overlap between sequences that drive nuclear enrichment in linear or circular contexts. Binding of specific RBPs underpins some of these differences - SRSF1 binding leads to nuclear enrichment of circular RNAs SAFB binding is associated with nuclear enrichment of predominantly unspliced RNAs and IGF2BP1 promotes export of linear spliced RNA molecules. The post-transcriptional fate of long RNAs is thus dictated by combinatorial contribution of RNA processing and sequence elements.