The RNA-binding protein SFPQ preserves long-intron splicing and regulates circRNA biogenesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA662248 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12606813.fastq.gz | Fastqsanger.gz | |||
| SRR12606814.fastq.gz | Fastqsanger.gz | |||
| SRR12606815.fastq.gz | Fastqsanger.gz | |||
| SRR12606816.fastq.gz | Fastqsanger.gz | |||
| SRR12606817.fastq.gz | Fastqsanger.gz |
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Project description:Circular RNAs (circRNAs) represent an abundant and conserved entity of non-coding RNAs; however, the principles of biogenesis are currently not fully understood. Here, we identify two factors, splicing factor proline/glutamine rich (SFPQ) and non-POU domain-containing octamer-binding protein (NONO), to be enriched around circRNA loci. We observe a subclass of circRNAs, coined DALI circRNAs, with distal inverted Alu elements and long flanking introns to be highly deregulated upon SFPQ knockdown. Moreover, SFPQ depletion leads to increased intron retention with concomitant induction of cryptic splicing, premature transcription termination, and polyadenylation, particularly prevalent for long introns. Aberrant splicing in the upstream and downstream regions of circRNA producing exons are critical for shaping the circRNAome, and specifically, we identify missplicing in the immediate upstream region to be a conserved driver of circRNA biogenesis. Collectively, our data show that SFPQ plays an important role in maintaining intron integrity by ensuring accurate splicing of long introns, and disclose novel features governing Alu-independent circRNA production.
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Project description:Circular RNAs (circRNAs) are natural outputs of eukaryotic transcription and RNA processing and have emerged as critical regulators in physiology and human diseases. Although a series of cis-elements and trans-factors are reported to globally regulate circRNA biogenesis, most of these regulations are unconserved or at most mammalian conserved. Here, using a genome-wide CRISPR knockout screen, we have identified an evolutionarily conserved polyadenosine RNA-binding protein ZC3H14 to regulate circRNA biogenesis in eukaryotes. Mechanistically, ZC3H14 associates with spliceosome to bind to 3' and 5' exon-intron boundaries of circularized exons, and forms a dimer to promote circRNA biogenesis. ZC3H14 knockout mice exhibit disrupted spermatogenesis and reduced testicular circRNA levels. Additionally, human ZC3H14 is associated with male infertility. Our findings reveal a conserved requirement for ZC3H14/Nab2 in the modulation of eukaryotic backsplicing and link ZC3H14 along with circRNAs to mammalian testicular disorders.
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Project description:MicroRNAs (miRNAs) play crucial roles in physiological functions and diseases such as cancer, but the regulation of their nuclear biogenesis remains poorly understood. Here, BioID on Drosha, the catalytic subunit of the microprocessor complex, revealed its proximity to SFPQ, a multifunctional RNA-binding protein (RBP) notably involved in forming the paraspeckle nuclear condensates. SFPQ depletion impacted both primary and mature miRNA expression, while other crucial paraspeckle proteins or the paraspeckle scaffolding lncRNA NEAT1 did not, indicating a unique paraspeckle-independent role. Comprehensive transcriptomic analyses showed that SFPQ loss broadly affects RNA and miRNA host gene (miRNA HG) expression, influencing both their transcription and stability. Notably, SFPQ protects specific miRNA HGs, including the oncogenic miR-17~92 polycistron, from degradation by the nuclear NEXT-exosome complex. Lastly, we show that high SFPQ is tightly linked with overexpression miR-17~92 and its mature miRNAs across a broad variety of cancers. Our findings reveal a dual role for SFPQ in the regulation of miRNA HGs transcription and stability, as well as its significance in cancers.
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Project description:MicroRNAs (miRNAs) play crucial roles in physiological functions and diseases such as cancer, but the regulation of their nuclear biogenesis remains poorly understood. Here, BioID on Drosha, the catalytic subunit of the microprocessor complex, revealed its proximity to SFPQ, a multifunctional RNA-binding protein (RBP) notably involved in forming the paraspeckle nuclear condensates. SFPQ depletion impacted both primary and mature miRNA expression, while other crucial paraspeckle proteins or the paraspeckle scaffolding lncRNA NEAT1 did not, indicating a unique paraspeckle-independent role. Comprehensive transcriptomic analyses showed that SFPQ loss broadly affects RNA and miRNA host gene (miRNA HG) expression, influencing both their transcription and stability. Notably, SFPQ protects specific miRNA HGs, including the oncogenic miR-17~92 polycistron, from degradation by the nuclear NEXT-exosome complex. Lastly, we show that high SFPQ is tightly linked with overexpression miR-17~92 and its mature miRNAs across a broad variety of cancers. Our findings reveal a dual role for SFPQ in the regulation of miRNA HGs transcription and stability, as well as its significance in cancers.
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