Altered nucleocytoplasmic export of adenosine (A)-rich circRNAs by PABPC1 contributes to neuronal function
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ABSTRACT:
PROVIDER: PRJNA1104751 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28810700_1.fastq.gz | Fastqsanger.gz | |||
| SRR28810700_2.fastq.gz | Fastqsanger.gz | |||
| SRR28810695_1.fastq.gz | Fastqsanger.gz | |||
| SRR28810695_2.fastq.gz | Fastqsanger.gz | |||
| SRR28810696_1.fastq.gz | Fastqsanger.gz |
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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
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 | GSE265930 | GEO
Project description:Altered nucleocytoplasmic export of adenosine (A)-rich circRNAs by PABPC1 contributes to neuronal function [FB_KD_circRTN4_RNAseq]
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Project description:Eukaryotic mRNAs undergo a cycle of transcription, nuclear export, and degradation. A major challenge is to obtain a global, quantitative view of these processes. Here we measured the genome-wide nucleocytoplasmic dynamics of mRNA in Drosophila cells by metabolic labeling in combination with cellular fractionation. By mathematical modeling of these data we determined rates of transcription, export and cytoplasmic decay for >5,000 genes. We characterized these kinetic rates and investigated links with mRNA features, RNA-binding proteins (RBPs) and chromatin states. We found prominent correlations between mRNA decay rate and transcript size, while nuclear export rates are linked to the size of the 3'UTR. Transcription, export and decay rates are each associated with distinct spectra of RBPs. Specific classes of genes, such as those encoding cytoplasmic ribosomal proteins, exhibit characteristic combinations of rate constants, suggesting modular control. Overall, transcription and decay rates have a major impact on transcript abundance, while nuclear export is of minor importance. Finally, correlations between rate constants suggest global coordination between the three processes. Our approach should be generally applicable to other cell systems and provides insights into the genome-wide nucleocytoplasmic kinetics of mRNA.
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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.
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Project description: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.
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Project description:Proper nucleocytoplasmic distribution of proteins is essential to cellular homeostasis but what role the altered nuclear export machinery commonly described in cancer cells plays in cancer initiation is not known. Here, genomic analysis of 42,793 cancers identified recurrent mutational hotspots in XPO1, the main nuclear export receptor in eukaryotic cells. Expression of XPO1 mutations in vivo was sufficient to initiate clonal, B-lymphoproliferative disorders by altering the constellation of proteins exported from the nucleus based on amino acid charge C-terminal to their nuclear export signal. Impaired export of one such protein, the NFkB inhibitor IB enhanced NFkB signaling, a pathway frequently activated by somatic mutations in cancers enriched in XPO1 mutations. These data identify change-of-function mutations in nuclear export as novel drivers of tumorigenesis.
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Project description:To explore the overall circRNAs involved in growth and development of Arabidopsis thaliana across the lifespan, we deeply sequenced samples of whole plants from different developmental stages (cotyledons emergence, rosette leavesï¹¥1 mm, rosette growth complete, first flower open, flourishing florescence, first silique shattered, senescence). The total RNA was purified by rRNA-depletion and linear RNA removal with RNAseR, and sequenced by the Illumina HiSeq2500 platform. We obtained 31 Gb raw data and identified 1217 circRNAs with expression quantity. We annotated these circRNAs and predicted their targeted microRNA. The circRNAs involved in growth and development of Arabidopsis thaliana across lifespan were identified and analyzed using the Illumina HiSeq2500 platform.
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Project description:Spinocerebellar Ataxia Type 2 (SCA2) is caused by expansion of a polyglutamine encoding triplet repeat in the human ATXN2 gene beyond (CAG)31. This is thought to mediate toxic gain-of-function by protein aggregation, and affect RNA processing, resulting in degenerative processes affecting preferentially cerebellar neurons. As a faithful animal model, we generated a knock-in mouse replacing the single CAG of murine Atxn2 with CAG42, a frequent patient genotype. This expansion size was inherited stably. The mice showed phenotypes with reduced weight and later motor incoordination. Although brain Atxn2 mRNA became elevated, soluble ATXN2 protein levels diminished over time, which might explain partial loss-of-function effects. Deficits in soluble ATXN2 protein correlated with the appearance of insoluble ATXN2, a progressive feature in cerebellum possibly reflecting toxic gains-of-function. Since in vitro ATXN2 overexpression was known to reduce levels of its protein interactor PABPC1, we studied expansion effects on PABPC1. In cortex, PABPC1 transcript, soluble and insoluble protein levels were increased. In more vulnerable cerebellum the progressive insolubility of PABPC1 was accompanied by decreased soluble protein levels, with PABPC1 mRNA showing no compensatory increase. The sequestration of PABPC1 into insolubility by ATXN2 function gains was validated in human cell culture. To understand consequences on mRNA processing, transcriptome profiles at medium and old age in three different tissues were studied and demonstrated selective induction of Fbxw8 in old cerebellum. Fbxw8 is encoded next to the Atxn2 locus and was shown in vitro to decrease the level of expanded insoluble ATXN2 protein. In conclusion, our data support the concept that expanded ATXN2 undergoes progressive insolubility and affects PABPC1 by a toxic gain-of-function mechanism with tissue-specific effects, which may be partially alleviated by the induction of FBXW8. Factorial design comparing Atxn2 knock-in mice with wild type littermates in three different tissues (brainstem, cerebellum, liver)
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