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Nuclear export of circular RNA

ABSTRACT: Circular RNAs (circRNAs), which are increasingly being implicated in a variety of functions in normal and cancerous cells1-5, are formed by back-splicing of precursor mRNAs in the nucleus6-10. circRNAs are predom¬inantly localized in the cytoplasm, indicating that they must be exported from the nucleus. Here, we uncover a pathway specific for nuclear export of circular RNA. This pathway requires Ran-GTP, Exportin-2 and IGF2BP1. Enhancing the nuclear Ran-GTP gradient by depletion or chemical inhibition of the major protein exporter, CRM1, selectively increases nuclear export of circRNAs, while reducing the nuclear Ran-GTP gradient selectively blocks circRNA export. Depletion or knockout of Exportin-2 specifically inhibits nuclear export of circRNA. Analysis of nuclear circRNA binding proteins reveals that interaction of IGF2BP1 with circRNA is enhanced by Ran-GTP. Formation of circRNA export complexes in the nucleus is promoted by Ran-GTP through its interactions with IGF2BP1, Exportin-2 and circRNA. Our findings demonstrate that adaptors such as IGF2BP1 that bind directly to circular RNAs recruit Ran-GTP and Exportin-2 to export circRNAs in a mechanism analogous to protein export, rather than mRNA export.

ORGANISM(S): Homo sapiens

PROVIDER: GSE226716 | GEO | 2023/11/22

REPOSITORIES: GEO

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Nuclear export of circular RNA

Project description:Circular RNAs (circRNAs), which can function as regulators of gene expression, are formed by back-splicing of precursor mRNAs in the nucleus. circRNAs are predominantly localized in the cytoplasm, indicating that they must be exported from the nucleus. Here, we uncover a pathway specific for nuclear export of circular RNA. This pathway requires Ran-GTP, Exportin-2 and IGF2BP1. Enhancing the nuclear Ran-GTP gradient by depletion or chemical inhibition of the major protein exporter, CRM1, selectively increases nuclear export of circRNAs, while reducing the nuclear Ran-GTP gradient selectively blocks circRNA export. Analysis of nuclear circRNA binding proteins reveals that interaction of IGF2BP1 with circRNA is enhanced by Ran-GTP, whereas its interaction with linear RNA is inhibited by Ran-GTP. Depletion or knockout of Exportin-2 specifically inhibits nuclear export of circRNA, while formation of an Exportin-2 circRNA export complex requires Ran-GTP and IGF2BP1. Our findings demonstrate that adaptors such as IGF2BP1 that bind directly to circular RNAs recruit Exportin-2 to export circRNAs in a mechanism analogous to protein export, rather than mRNA export.

2023-12-09 | GSE235899 | GEO

DNA-RNA IP sequencing for R-loops in XPO4 Knockout NIH/3T3 cell

Project description:Numerous RNAs are exported from the nucleus, abnormalities of which lead to cellular complications and diseases. We report the identification of Exportin 4 (XPO4) as a conserved circular RNA (circRNA) exportin. Cellular insufficiency of XPO4 causes nuclear circRNA accumulation, circRNA:DNA (ciR-loop) formation, linear RNA:DNA (liR-loop) buildup, and DNA damage. These results provide insights into the mechanism and biomedical links of circRNA nuclear export.

2022-08-12 | GSE196317 | GEO

High throughput sequencing for circRNAs and mRNAs in XPO4 knockout NIH/3T3 cell [RNA-seq]

2022-08-12 | GSE196318 | GEO

Neural circular RNAs are derived from synaptic genes and regulated by development and plasticity

Project description:Circular RNAs (circRNAs), formed by the atypical head-to-tail splicing of exons, have re-emerged as a potentially interesting RNA species given recent reports of a surprising diversity and abundance of circRNA in organisms ranging from worm to human. Here, using deep RNA sequencing, we profiled different RNA species in mouse and observed that circRNAs are significantly enriched in neural tissue, relative to other tissues. Using PacBio sequencing, we determined, for the first time, the circular structure of this population of circRNAs as well as their full-length sequences. We discovered that a disproportionate fraction of the brain circRNA population is derived from host genes that code for synaptic proteins. Moreover, based on the separate profiling of the RNAs localized in neuronal cell bodies and neuropil (enriched in axons and dendrites), we found that, on average, circular RNAs are more enriched in the neuropil than their host gene mRNA isoforms. Using high resolution in situ hybridization we, for the first time, directly visualized circRNA punctae in the dendrites of neurons. The host gene origin and location of the circRNA in neurons suggest the possibility that circRNAs might participate in the regulation of synaptic function and plasticity. Consistent with this idea, we observed via profiling at different developmental stages, that the abundance of many circular RNAs changes abruptly at a time corresponding to synaptogenesis. In addition, following a homeostatic downscaling of neuronal activity many circRNAs exhibit significant up or down-regulation. These data indicate that brain circRNAs are positioned to respond to and regulate synaptic function. Circular RNA profiling in 13 different samples in mice and four samples in rat, using Illumina sequencing

2015-02-25 | E-GEOD-61991 | biostudies-arrayexpress

Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals

Project description:Circular RNAs (circRNAs) are a large class of animal RNAs. To investigate possible circRNA functions, it is important to understand circRNA biogenesis. Besides human Alu repeats, sequence features that promote exon circularization are largely unknown. We experimentally identified new circRNAs in C. elegans. Reverse complementary sequences between introns bracketing circRNAs were significantly enriched compared to linear controls. By scoring the presence of reverse complementary sequences in human introns we predicted and experimentally validated novel circRNAs. We show that introns bracketing circRNAs are highly enriched in RNA editing or hyper-editing events. Knockdown of the double-strand RNA editing ADAR1 enzyme significantly and specifically up-regulated circRNA expression. Together, our data support a model of animal circRNA biogenesis in which competing RNA:RNA interactions of introns form larger structures which promote circularization of embedded exons, while ADAR1 antagonizes circRNA expression by melting stems within these interactions. Thus, we assign a new function to ADAR1. Examination of 12 samples in different stages of C.elegans development.

2015-01-06 | E-GEOD-63823 | biostudies-arrayexpress

Exportin Crm1 is repurposed as a docking protein to generate microtubule organizing centers at the nuclear pore

Project description:Non-centrosomal microtubule organizing centers (MTOCs) are important for microtubule organization in many cell types. In fission yeast Schizosaccharomyces pombe, the protein Mto1, together with partner protein Mto2 (Mto1/2 complex), recruits the g-tubulin complex to multiple non-centrosomal MTOCs, including the nuclear envelope (NE). Here, we develop a comparative-interactome mass spectrometry approach to determine how Mto1 localizes to the NE. Surprisingly, we find that Mto1, a constitutively cytoplasmic protein, docks at nuclear pore complexes (NPCs), via interaction with exportin Crm1 and cytoplasmic FG-nucleoporin Nup146. Although Mto1 is not a nuclear export cargo, it binds Crm1 via a nuclear export signal-like sequence, and docking requires both Ran in the GTP-bound state and Nup146 FG repeats. In addition to determining the mechanism of MTOC formation at the NE, our results reveal a novel role for Crm1 and the nuclear export machinery in the stable docking of a cytoplasmic protein complex at NPCs.

2018-05-22 | PXD008334 | Pride

Altered nucleocytoplasmic export of adenosine (A)-rich circRNAs by PABPC1 contributes to neuronal function

Project description:Circular RNAs (circRNAs) are upregulated during neurogenesis. Where and how circRNAs are localized, and what roles they play during this process have remained elusive. By comparing the nuclear and cytoplasmic circRNAs between H9 cells and H9-derived forebrain neurons (FB), we found a subset of adenosine (A)-rich circRNAs are restricted in H9 nuclei but exported to cytosols upon forebrain neuron differentiation. This differentiation-coupled circRNA subcellular relocation is modulated by the poly(A)-binding protein PABPC1. In the nucleus, newly produced (A)-rich circRNAs are bound by PABPC1 and the nuclear basket protein TPR to prevent their nucleocytoplasmic export. Modulation of (A)-rich motifs in circRNAs remarkably alters their subcellular localization. Enforced (A)-rich circRNAs in cytosols result in mRNA translation suppression. Furthermore, decreased nuclear PABPC1 upon neuronal differentiation enables the export of (A)-rich circRNAs including circRTN4(2,3), which is required for neurite outgrowth. These findings uncover subcellular localization features of circRNAs, linking their processing and function during neurogenesis.

2024-04-30 | GSE265924 | GEO

Altered nucleocytoplasmic export of adenosine (A)-rich circRNAs by PABPC1 contributes to neuronal function [FB_KD_circRTN4_RNAseq]

2024-04-30 | GSE265930 | GEO

Microarray expression profile analysis of circular RNAs in human pancreatic ductal adenocarcinoma

Project description:To explore the potential involvement of circular RNAs (circRNAs) in pancreatic ductal adenocarcinoma (PDAC) oncogenesis, we conducted circRNA profiling in six pairs of human PDAC and adjacent normal tissue by microarray. Our results showed that clusters of circRNAs were aberrantly expressed in PDAC compared with normal samples, and provided potential targets for future treatment of PDAC and novel insights into PDAC biology. Analyze circular RNA expression in pancreatic ductal adenocarcinoma (PDAC) by microarray platform.

2015-11-20 | E-GEOD-69362 | biostudies-arrayexpress

Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed

Project description:Circular RNAs (circRNAs) are an endogenous class of animal RNAs. Despite their abundance, their function and expression in the nervous system are unknown. Therefore, we sequenced RNA from different brain regions, primary neurons, isolated synapses, as well as during neuronal differentiation. Using these and other available data, we discovered and analyzed thousands of neuronal human and mouse circRNAs. circRNAs were extraordinarily enriched in the mammalian brain, well conserved in sequence, often expressed as circRNAs in both human and mouse, and sometimes even detected in Drosophila brains. circRNAs were overall upregulated during neuronal differentiation, highly enriched in synapses, and often differentially expressed compared to their mRNA isoforms. circRNA expression correlated negatively with expression of the RNA-editing enzyme ADAR1. Knockdown of ADAR1 induced elevated circRNA expression. Together, we provide a circRNA brain expression atlas and evidence for important circRNA functions and values as biomarkers. To assess circRNA expression in mammalian brain, we sequenced and analyzed mouse brain regions (hippocampus, cerebellum, prefrontal cortex and olfactory bulb), various neuronal differentiation (mouse P19 and human SH-SY5Y cells) and maturation (mouse cortical neurons) stages, and subcellular compartments in mouse (synaptoneurosomal fraction, cytoplasmic fraction, whole brain lysate).

2015-04-24 | E-GEOD-65926 | biostudies-arrayexpress

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