Circular RNAs are long-lived and display only minimal early alterations in response to a growth factor

Abstract

Circular RNAs (circRNAs) are widespread circles of non-coding RNAs with largely unknown function. Because stimulation of mammary cells with the epidermal growth factor (EGF) leads to dynamic changes in the abundance of coding and non-coding RNA molecules, and culminates in the acquisition of a robust migratory phenotype, this cellular model might disclose functions of circRNAs. Here we show that circRNAs of EGF-stimulated mammary cells are stably expressed, while mRNAs and microRNAs change within minutes. In general, the circRNAs we detected are relatively long-lived and weakly expressed. Interestingly, they are almost ubiquitously co-expressed with the corresponding linear transcripts, and the respective, shared promoter regions are more active compared to genes producing linear isoforms with no detectable circRNAs. These findings imply that altered abundance of circRNAs, unlike changes in the levels of other RNAs, might not play critical roles in signaling cascades and downstream transcriptional networks that rapidly commit cells to specific outcomes.

MYC-containing amplicons in acute myeloid leukemia: Genomic structures, evolution, and transcriptional consequences

“…Remarkably, the transcriptional plasticity observed in our AML-amp cohort also includes circRNAs originated by back-splicing events 51 , resistant to exonucleolytic degradation 52 , and accumulating at relatively high levels within cells 47 58 . circPVT1, generated from exon 2 of PVT1, was found as highly expressed in HeLa cervical cancer cells, human proliferating fibroblasts 59 , and gastric cancer cells often accompanied by 8q24 amplifications 53 .…”

Circular RNAs: Unexpected outputs of many protein-coding genes

“…Due to their natural resistance to exonucleases, circular RNAs appear to be very stable transcripts with half-lives greater than 24-48 hr. 14,30 This is significantly longer than the half-life of an average mRNA (8-9 hr in human cells). 63,64 Nevertheless, the efficiency of backsplicing is far less than canonical splicing, 39 which makes many circular RNAs infrequently generated and unable to be rapidly induced, e.g.…”

“…Circular RNAs are naturally resistant to degradation by exonucleases and thus accumulate as stable transcripts. In at least 2 cases (CDR1as/ciRS-7 and Sry), circular RNAs function to sponge specific microRNAs, [26][27][28] although most circular RNAs (outside of Drosophila 29 ) contain few microRNA binding sites 30,31 and likely have a different function. For example, circular RNAs may allow the formation of large RNA-protein complexes, e.g., at neuronal synapses, 32,33 or possibly be translated.…”

“…29,61 Most circular RNAs are present at low levels, 31 and have been estimated to be, on average, <3% of the abundance of the canonical linear transcript from the same gene. 30 Nevertheless, there are hundreds of circular RNAs that are expressed at levels >10-fold higher than their corresponding linear transcript, 14 especially in the brain. 25,29,32,33,62 Circular RNAs are stable, but their biogenesis is slow…”

Circulating Circles Predict Postoperative Atrial Fibrillation

“…This unusual class of RNA circles is generated by the canonical spliceosome machinery, by a backsplicing event of 2 exons, which results in a covalently closed, single‐stranded RNA molecule. Because of their circular form, circRNAs are protected from ribonucleases and have greater stability than their linear counterparts 8. In the heart alone, thousands of different circRNAs are expressed 9.…”