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      A length-dependent evolutionarily conserved pathway controls nuclear export of circular RNAs

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          Abstract

          Here, Huang et al. investigated how circRNA localization or nuclear export is controlled and, using RNAi screening, found that depletion of the Drosophila DExH/D-box helicase Hel25E results in nuclear accumulation of long (>800-nt), but not short, circRNAs. Their findings suggest that the lengths of mature circRNAs are measured to dictate the mode of nuclear export.

          Abstract

          Circular RNAs (circRNAs) are generated from many protein-coding genes. Most accumulate in the cytoplasm, but how circRNA localization or nuclear export is controlled remains unclear. Using RNAi screening, we found that depletion of the Drosophila DExH/D-box helicase Hel25E results in nuclear accumulation of long (>800-nucleotide), but not short, circRNAs. The human homologs of Hel25E similarly regulate circRNA localization, as depletion of UAP56 (DDX39B) or URH49 (DDX39A) causes long and short circRNAs, respectively, to become enriched in the nucleus. These data suggest that the lengths of mature circRNAs are measured to dictate the mode of nuclear export.

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          Circular RNAs are a large class of animal RNAs with regulatory potency.

          Sebastian Memczak, Marvin Jens, Antigoni Elefsinioti … (2013)
          Circular RNAs (circRNAs) in animals are an enigmatic class of RNA with unknown function. To explore circRNAs systematically, we sequenced and computationally analysed human, mouse and nematode RNA. We detected thousands of well-expressed, stable circRNAs, often showing tissue/developmental-stage-specific expression. Sequence analysis indicated important regulatory functions for circRNAs. We found that a human circRNA, antisense to the cerebellar degeneration-related protein 1 transcript (CDR1as), is densely bound by microRNA (miRNA) effector complexes and harbours 63 conserved binding sites for the ancient miRNA miR-7. Further analyses indicated that CDR1as functions to bind miR-7 in neuronal tissues. Human CDR1as expression in zebrafish impaired midbrain development, similar to knocking down miR-7, suggesting that CDR1as is a miRNA antagonist with a miRNA-binding capacity ten times higher than any other known transcript. Together, our data provide evidence that circRNAs form a large class of post-transcriptional regulators. Numerous circRNAs form by head-to-tail splicing of exons, suggesting previously unrecognized regulatory potential of coding sequences.
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            Natural RNA circles function as efficient microRNA sponges.

            Thomas B. Hansen, Trine I. Jensen, Bettina H. Clausen … (2013)
            MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression that act by direct base pairing to target sites within untranslated regions of messenger RNAs. Recently, miRNA activity has been shown to be affected by the presence of miRNA sponge transcripts, the so-called competing endogenous RNA in humans and target mimicry in plants. We previously identified a highly expressed circular RNA (circRNA) in human and mouse brain. Here we show that this circRNA acts as a miR-7 sponge; we term this circular transcript ciRS-7 (circular RNA sponge for miR-7). ciRS-7 contains more than 70 selectively conserved miRNA target sites, and it is highly and widely associated with Argonaute (AGO) proteins in a miR-7-dependent manner. Although the circRNA is completely resistant to miRNA-mediated target destabilization, it strongly suppresses miR-7 activity, resulting in increased levels of miR-7 targets. In the mouse brain, we observe overlapping co-expression of ciRS-7 and miR-7, particularly in neocortical and hippocampal neurons, suggesting a high degree of endogenous interaction. We further show that the testis-specific circRNA, sex-determining region Y (Sry), serves as a miR-138 sponge, suggesting that miRNA sponge effects achieved by circRNA formation are a general phenomenon. This study serves as the first, to our knowledge, functional analysis of a naturally expressed circRNA.
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              Circular RNAs are abundant, conserved, and associated with ALU repeats.

              W. R. Jeck, J A Sorrentino, K. Wang … (2013)
              Circular RNAs composed of exonic sequence have been described in a small number of genes. Thought to result from splicing errors, circular RNA species possess no known function. To delineate the universe of endogenous circular RNAs, we performed high-throughput sequencing (RNA-seq) of libraries prepared from ribosome-depleted RNA with or without digestion with the RNA exonuclease, RNase R. We identified >25,000 distinct RNA species in human fibroblasts that contained non-colinear exons (a "backsplice") and were reproducibly enriched by exonuclease degradation of linear RNA. These RNAs were validated as circular RNA (ecircRNA), rather than linear RNA, and were more stable than associated linear mRNAs in vivo. In some cases, the abundance of circular molecules exceeded that of associated linear mRNA by >10-fold. By conservative estimate, we identified ecircRNAs from 14.4% of actively transcribed genes in human fibroblasts. Application of this method to murine testis RNA identified 69 ecircRNAs in precisely orthologous locations to human circular RNAs. Of note, paralogous kinases HIPK2 and HIPK3 produce abundant ecircRNA from their second exon in both humans and mice. Though HIPK3 circular RNAs contain an AUG translation start, it and other ecircRNAs were not bound to ribosomes. Circular RNAs could be degraded by siRNAs and, therefore, may act as competing endogenous RNAs. Bioinformatic analysis revealed shared features of circularized exons, including long bordering introns that contained complementary ALU repeats. These data show that ecircRNAs are abundant, stable, conserved and nonrandom products of RNA splicing that could be involved in control of gene expression.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Genes Dev
                Journal ID (iso-abbrev): Genes Dev
                Journal ID (hwp): genesdev
                Journal ID (pmc): genesdev
                Journal ID (publisher-id): GAD
                Title: Genes & Development
                Publisher: Cold Spring Harbor Laboratory Press
                ISSN (Print): 0890-9369
                ISSN (Electronic): 1549-5477
                Publication date (Print): 1 May 2018
                Volume: 32
                Issue: 9-10
                Pages: 639-644
                Affiliations
                Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA
                Author notes
                Author information
                http://orcid.org/0000-0001-6929-8755
                Article
                Medline ID: 8711660
                DOI: 10.1101/gad.314856.118
                PMC ID: 6004072
                PubMed ID: 29773557
                SO-VID: eaf76b53-f981-403b-a173-284f661b3ef8
                Copyright © © 2018 Huang et al.; Published by Cold Spring Harbor Laboratory Press
                License:

                This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

                History
                Date received : 26 March 2018
                Date accepted : 24 April 2018
                Page count
                Pages: 6
                Funding
                Funded by: University of Pennsylvania , open-funder-registry 10.13039/100006920;
                Funded by: National Institutes of Health , open-funder-registry 10.13039/100000002;
                Award ID: R00-GM104166
                Award ID: R35-GM119735
                Categories
                Subject: Research Communication

                Keywords: circrna,hel25e,uap56,urh49,ddx39a,ddx39b
                Data availability:
                Keywords: circrna, hel25e, uap56, urh49, ddx39a, ddx39b

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