scholarly journals The RNA-binding protein SFPQ preserves long-intron splicing and regulates circRNA biogenesis in mammals

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Lotte Victoria Winther Stagsted ◽  
Eoghan Thomas O'Leary ◽  
Karoline Kragh Ebbesen ◽  
Thomas Birkballe Hansen
Keyword(s):  
Rna Binding ◽  
Binding Protein ◽  
Intron Retention ◽  
Transcription Termination ◽  
Upstream Region ◽  
Circular Rnas ◽  
Aberrant Splicing ◽  
Pou Domain ◽  
Two Factors ◽  
Non Coding Rnas

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.

scholarly journals The RNA-binding protein SFPQ preserves long-intron splicing and regulates circRNA biogenesis

2020 ◽  
Author(s):  
Lotte Victoria Winther Stagsted ◽  
Eoghan Thomas O’Leary ◽  
Thomas Birkballe Hansen
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Intron Retention ◽  
Transcription Termination ◽  
Upstream Region ◽  
Circular Rnas ◽  
Aberrant Splicing ◽  
Two Factors ◽  
Negative Effect ◽  
Non Coding Rnas

AbstractCircular RNAs (circRNAs) represent an abundant and conserved entity of non-coding RNAs, however the principles of biogenesis are currently not fully understood. To elucidate features important for circRNA production, we performed global analyses of RNA-binding proteins associating with the flanking introns of circRNAs, and we identified two factors, SFPQ and NONO, to be highly enriched with circRNAs. Using transient knockdown of both proteins in two human cell lines followed by total RNAseq, we found a subclass of circRNAs with distal inverted Alu elements and long introns to be highly deregulated upon SFPQ knockdown. In addition, SFPQ depletion leads to increased intron retention with concomitant induction of cryptic splicing prevalent for long introns causing in some cases premature transcription termination and polyadenylation. While SFPQ depletion has an overall negative effect on circRNA production, premature termination is not the main causative explanation. Instead, data suggests that aberrant splicing in the upstream and downstream regions of circRNA producing exons are critical for shaping the circRNAome, and specifically, we observe a conserved impact of missplicing in the immediate upstream region to drive 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.

scholarly journals The effective function of circular RNA in colorectal cancer

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Mandana Ameli-Mojarad ◽  
Melika Ameli-Mojarad ◽  
Mahrooyeh Hadizadeh ◽  
Chris Young ◽  
Hosna Babini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Circular Rna ◽  
Circular Rnas ◽  
Colorectal Tumorigenesis ◽  
Non Coding Rnas ◽  
Mirna Sponges ◽  
Mechanisms Of Development

AbstractColorectal cancer (CRC) is the 3rd most common type of cancer worldwide. Late detection plays role in one-third of annual mortality due to CRC. Therefore, it is essential to find a precise and optimal diagnostic and prognostic biomarker for the identification and treatment of colorectal tumorigenesis. Covalently closed, circular RNAs (circRNAs) are a class of non-coding RNAs, which can have the same function as microRNA (miRNA) sponges, as regulators of splicing and transcription, and as interactors with RNA-binding proteins (RBPs). Therefore, circRNAs have been investigated as specific targets for diagnostic and prognostic detection of CRC. These non-coding RNAs are also linked to metastasis, proliferation, differentiation, migration, angiogenesis, apoptosis, and drug resistance, illustrating the importance of understanding their involvement in the molecular mechanisms of development and progression of CRC. In this review, we present a detailed summary of recent findings relating to the dysregulation of circRNAs and their potential role in CRC.

scholarly journals The atypical RNA-binding protein TAF15 regulates dorsoanterior neural development through diverse mechanisms in Xenopus tropicalis.

2021 ◽  
Author(s):  
Caitlin S DeJong ◽  
Darwin S Dichmann ◽  
Cameron R.T. Exner ◽  
Yuxiao Xu ◽  
Richard M Harland
Keyword(s):  
Gene Regulation ◽  
Neural Development ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Intron Retention ◽  
Transcript Abundance ◽  
Fused In Sarcoma ◽  
Neural Tissues ◽  
Ewings Sarcoma

The FET family of atypical RNA-binding proteins includes Fused in sarcoma (Fus), Ewings sarcoma (EWS), and the TATA-binding protein-associate factor 15 (TAF15). All FET family members are highly conserved from fish to mammals, suggesting an independent and specialized requirement for each protein. Fus is necessary for the proper splicing of genes required for mesoderm differentiation and cell adhesion in Xenopus, but the role, if any, that EWS and TAF15 play in development remains unknown. Here we define the role maternally deposited and zygotically transcribed TAF15 plays in development. We find that TAF15 is essential for the proper development of dorsoanterial neural tissues, and by sequencing the RNA from single TAF15-depleted embryos and measuring changes in transcript abundance and exon usage we found TAF15 regulates dorsoanterior neural tissue development through regulating fgfr4 and ventx2.1. Intriguingly, we find that TAF15 uses two distinct mechanisms to downregulate FGFR4 expression: 1) retention of a single intron within fgfr4 and 2) reduction of total fgfr4 transcript. Intron retention was identified when both maternal and zygotic TAF15 is depleted, while depletion of zygotic TAF15 alone leads to regulation of fgfr4 total transcripts. In this study we find that TAF15 plays an integral and pleiotropic role in the development of dorsoanterior neural tissues and further identify two novel mechanisms of gene regulation by TAF15, suggesting TAF15 gene regulation is target and cofactor-dependent, subject to the milieu of factors that are present at different times of development.

scholarly journals New Insights into the Interplay between Non-Coding RNAs and RNA-Binding Protein HnRNPK in Regulating Cellular Functions

Cells ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 62 ◽  
Author(s):  
Yongjie Xu ◽  
Wei Wu ◽  
Qiu Han ◽  
Yaling Wang ◽  
Cencen Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mammalian Cells ◽  
Rna Binding ◽  
Binding Protein ◽  
Genomic Structure ◽  
Rna Binding Protein ◽  
Stem Cell Differentiation ◽  
Cellular Functions ◽  
Non Coding Rnas ◽  
Conserved Gene

The emerging data indicates that non-coding RNAs (ncRNAs) epresent more than the “junk sequences” of the genome. Both miRNAs and long non-coding RNAs (lncRNAs) are involved in fundamental biological processes, and their deregulation may lead to oncogenesis and other diseases. As an important RNA-binding protein (RBP), heterogeneous nuclear ribonucleoprotein K (hnRNPK) is known to regulate gene expression through the RNA-binding domain involved in various pathways, such as transcription, splicing, and translation. HnRNPK is a highly conserved gene that is abundantly expressed in mammalian cells. The interaction of hnRNPK and ncRNAs defines the novel way through which ncRNAs affect the expression of protein-coding genes and form autoregulatory feedback loops. This review summarizes the interactions of hnRNPK and ncRNAs in regulating gene expression at transcriptional and post-transcriptional levels or by changing the genomic structure, highlighting their involvement in carcinogenesis, glucose metabolism, stem cell differentiation, virus infection and other cellular functions. Drawing connections between such discoveries might provide novel targets to control the biological outputs of cells in response to different stimuli.

scholarly journals Potential Clinical Applications of Exosomal Circular RNAs: More than Diagnosis

2021 ◽  
Vol 8 ◽  
Author(s):  
Kearabetsoe Matseliso Molibeli ◽  
Rong Hu ◽  
Yuze Liu ◽  
Dehui Xiong ◽  
Lijun Tang
Keyword(s):  
Rna Binding ◽  
Neurological Diseases ◽  
Cell Communication ◽  
Clinical Applications ◽  
Circular Rnas ◽  
Control Gene Expression ◽  
Genome Wide ◽  
Potential Applications ◽  
Non Coding Rnas ◽  
Regulatory Functions

Exosomes are small vesicles derived from cells used as cell-to-cell communication goods in numerous diseases including tumorigenesis, neurological diseases, cardiovascular diseases and other diseases. Circular RNAs (circRNAs) are an innovative constituent of non-coding endogenous RNAs generated through backsplicing, catalyzed by RNA polymerase Ⅱ. These non-coding RNAs have been suggested to control gene expression through miRNA sponging, RNA-binding protein regulation and translational capabilities. Genome-wide RNA sequence analyses observed that circRNAs were stably improved in exosomes in association to parental cells. Little attention has been dedicated to exosomal circRNAs (exo-circRNAs). However, research has demonstrated that exo-circRNAs may have important regulatory functions because of their stability in cells and within exosomes. If well understood, the precise roles and mechanisms of exo-circRNAs might surge the impending clinical applications of these molecules as markers in the identification, prediction and treatment of various diseases. In this review, we outline recent findings regarding exo-circRNAs which includes their functions and highlights their potential applications and therapeutic targets in human diseases.

scholarly journals The SRSF1/circATP5B/miR-185-5p/HOXB5 Feedback Loop Regulates the Proliferation of Glioma Stem Cells via the IL6-mediated JAK2/STAT3 Signaling Pathway

2020 ◽  
Author(s):  
Junshuang Zhao ◽  
Yang Jiang ◽  
Haiying Zhang ◽  
Jinpeng Zhou ◽  
Lian Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Feedback Loop ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Bioinformatic Analysis ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
Glioma Stem Cells ◽  
Stat3 Signaling

Abstract BackgroundGlioma is the most common and malignant tumor of central nervous system. The tumor initiation, self-renewal, and multi-lineage differentiation abilities of glioma stem cells (GSCs) are responsible for glioma proliferation and recurrence. Although circular RNAs (circRNAs) play vital roles in the progression of glioma, the detailed mechanisms remain unknown. MethodsqRT-PCR, western blotting, immunohistochemistry, and bioinformatic analysis were performed to detect the expression of circATP5B, miR-185-5p, HOXB5, and SRSF1. Patient-derived GSCs were established, and MTS, EDU, neurosphere formation, and limiting dilution assays were used to detect the proliferation of GSCs. RNA-binding protein immunoprecipitation, RNA pull-down, luciferase reporter assays, and chromatin immunoprecipitation assays were used to detect these molecules' regulation mechanisms. ResultsWe found circATP5B expression was significantly upregulated in GSCs and promoted the proliferation of GSCs. Mechanistically, circATP5B acted as miR-185-5p sponge to upregulate HOXB5 expression. HOXB5 was overexpressed in glioma and transcriptionally regulated IL6 expression and promoted the proliferation of GSCs via JAK2/STAT3 signaling. Moreover, RNA binding protein SRSF1 could bind to and promote circATP5B expression and regulate the proliferation of GSCs, while HOXB5 also transcriptionally regulated SRSF1 expression. ConclusionsOur study identified the SRSF1/circATP5B/miR-185-5p/HOXB5 feedback loop in GSCs. This provides an effective biomarker for glioma diagnosis and prognostic evaluation.

scholarly journals Nuclear TARBP2 drives oncogenic dysregulation of RNA splicing and decay

2018 ◽  
Author(s):  
Lisa Fish ◽  
Hoang C.B. Nguyen ◽  
Steven Zhang ◽  
Myles Hochman ◽  
Brian D. Dill ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Transcription Factor ◽  
Rna Binding ◽  
Binding Protein ◽  
Intron Retention ◽  
Rna Stability ◽  
Rna Binding Protein ◽  
List Type ◽  
Gene Expression Control

SUMMARYPost-transcriptional regulation of RNA stability is a key step in gene expression control. We describe a regulatory program, mediated by the double-stranded RNA binding protein TARBP2, that controls RNA stability in the nucleus. TARBP2 binding to pre-mRNAs results in increased intron retention, subsequently leading to targeted degradation of TARBP2-bound transcripts. This is mediated by TARBP2 recruitment of the m6A RNA methylation machinery to its target transcripts, where deposition of m6A marks influences the recruitment of splicing regulators, inhibiting efficient splicing. Interactions between TARBP2 and the nucleoprotein TPR then promote degradation of these TARBP2-bound transcripts by the nuclear exosome. Additionally, analysis of clinical gene expression datasets revealed a functional role for this TARBP2 pathway in lung cancer. Using xenograft mouse models, we find that TARBP2 impacts tumor growth in the lung, and that this function is dependent on TARBP2-mediated destabilization of ABCA3 and FOXN3. Finally, we establish the transcription factor ZNF143 as an upstream regulator of TARBP2 expression.RESEARCH HIGHLIGHTSThe RNA-binding protein TARBP2 controls the stability of its target transcripts in the nucleusNuclear TARBP2 recruits the methyltransferase complex to deposit m6A marks on its target transcriptsTARBP2 and m6A-mediated interactions with splicing and nuclear RNA surveillance complexes result in target transcript intron retention and decay.Increased TARBP2 expression is associated with lung cancer and promotes lung cancer growthin vivo.The transcription factor ZNF143 drives oncogenic TARBP2 upregulation in lung cancer.

scholarly journals RNA-binding protein IGF2BP2 enhances circ_0000745 abundancy and promotes aggressiveness and stemness of ovarian cancer cells via the microRNA-3187-3p/ERBB4/PI3K/AKT axis

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Shengtan Wang ◽  
Zaihong Li ◽  
Genhai Zhu ◽  
Lan Hong ◽  
Chunyan Hu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Rna Binding ◽  
Epithelial Mesenchymal Transition ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Circular Rnas ◽  
Ovarian Cancer Cells ◽  
Loss Of Function ◽  
Mesenchymal Transition ◽  
Repressive Effect

Abstract Background Circular RNAs (circRNAs) are increasingly recognized as important regulators in cancer including ovarian cancer (OC). This work focuses on the effects of circ_0000745 on the OC development of and molecules involved. Methods Expression of circ_0000745 in collected OC tissues and the acquired OC cell lines was examined by RT-qPCR. The stability of circ_0000745 in cells was examined by RNase R treatment. The target transcripts interacted with circ_0000745 were predicted using bioinformatic systems. Gain- and loss-of-function studies of circ_0000745, microRNA (miR)-3187-3p and erb-b2 receptor tyrosine kinase 4 (ERBB4) were conducted to determine their functions on proliferation, migration, invasion and stem cell property of OC cells. Results Circ_0000745 and ERBB4 were abundantly expressed while miR-3187-3p was poorly expressed in OC tissues and cells. Circ_0000745 sequestered miR-3187-3p and blocked its repressive effect on ERBB4. Downregulation of circ_0000745 reduced proliferation, aggressiveness, epithelial-mesenchymal transition, and stemness of SK-OV-3 cells, but this reduction was blocked upon miR-3187-3p inhibition or ERBB4 upregulation. By contrast, artificial induction of circ_0000745 upregulation, miR-3187-3p upregulation and ERBB4 downregulation led to inverse trends in ES-2 cells. ERBB4 promoted the phosphorylation of the PI3K/AKT signaling pathway. An RNA binding protein IGF2BP2 was found to circ_0000745 bind to and promote its expression and stability. Conclusion This study demonstrated that circ_0000745 upregulated by IGF2BP2 promotes aggressiveness and stemness of OC cells through a miR-3187-3p/ERBB4/PI3K/AKT axis. Circ_0000745 may serve as a promising target for OC treatment.

scholarly journals The SRSF1/circATP5B/miR-185-5p/HOXB5 feedback loop regulates the proliferation of glioma stem cells via the IL6-mediated JAK2/STAT3 signaling pathway

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Junshuang Zhao ◽  
Yang Jiang ◽  
Haiying Zhang ◽  
Jinpeng Zhou ◽  
Lian Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Feedback Loop ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Bioinformatic Analysis ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
Glioma Stem Cells ◽  
Stat3 Signaling

Abstract Background Glioma is the most common and malignant tumor of central nervous system. The tumor initiation, self-renewal, and multi-lineage differentiation abilities of glioma stem cells (GSCs) are responsible for glioma proliferation and recurrence. Although circular RNAs (circRNAs) play vital roles in the progression of glioma, the detailed mechanisms remain unknown. Methods qRT-PCR, western blotting, immunohistochemistry, and bioinformatic analysis were performed to detect the expression of circATP5B, miR-185-5p, HOXB5, and SRSF1. Patient-derived GSCs were established, and MTS, EDU, neurosphere formation, and limiting dilution assays were used to detect the proliferation of GSCs. RNA-binding protein immunoprecipitation, RNA pull-down, luciferase reporter assays, and chromatin immunoprecipitation assays were used to detect these molecules’ regulation mechanisms. Results We found circATP5B expression was significantly upregulated in GSCs and promoted the proliferation of GSCs. Mechanistically, circATP5B acted as miR-185-5p sponge to upregulate HOXB5 expression. HOXB5 was overexpressed in glioma and transcriptionally regulated IL6 expression and promoted the proliferation of GSCs via JAK2/STAT3 signaling. Moreover, RNA binding protein SRSF1 could bind to and promote circATP5B expression and regulate the proliferation of GSCs, while HOXB5 also transcriptionally regulated SRSF1 expression. Conclusions Our study identified the SRSF1/circATP5B/miR-185-5p/HOXB5 feedback loop in GSCs. This provides an effective biomarker for glioma diagnosis and prognostic evaluation.

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