Altered nucleocytoplasmic export of adenosine (A)-rich circRNAs by PABPC1 contributes to neuronal function [FB_KD_circRTN4_RNAseq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1104987 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28818794_1.fastq.gz | Fastqsanger.gz | |||
| SRR28818794_2.fastq.gz | Fastqsanger.gz | |||
| SRR28818795_1.fastq.gz | Fastqsanger.gz | |||
| SRR28818795_2.fastq.gz | Fastqsanger.gz | |||
| SRR28818796_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.
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Project description:Altered nucleocytoplasmic export of adenosine (A)-rich circRNAs by PABPC1 contributes to neuronal function
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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: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.
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