scholarly journals An autoregulation loop in fust-1 for circular RNA regulation in Caenorhabditis elegans

Genetics ◽  
2021 ◽  
Author(s):  
Dong Cao
Keyword(s):  
Caenorhabditis Elegans ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Exon Skipping ◽  
Cell Types ◽  
Circular Rna ◽  
Circular Rnas ◽  
Fused In Sarcoma ◽  
Isoform B

Abstract Many circular RNAs (circRNAs) are differentially expressed in different tissues or cell types, suggestive of specific factors that regulate their biogenesis. Here, taking advantage of available mutation strains of RNA-binding proteins (RBPs) in Caenorhabditis elegans, I performed a screening of circRNA regulation in 13 conserved RBPs. Among them, loss of FUST-1, the homolog of Fused in Sarcoma (FUS), caused downregulation of multiple circRNAs. By rescue experiments, I confirmed FUST-1 as a circRNA regulator. Through RNA sequencing using circRNA-enriched samples, circRNAs targets regulated by FUST-1 were identified globally, with hundreds of them significantly altered. Furthermore, I showed that FUST-1 regulates circRNA formation with only small to little effect on the cognate linear mRNAs. When recognizing circRNA pre-mRNAs, FUST-1 can affect both exon-skipping and circRNA in the same genes. Moreover, I identified an autoregulation loop in fust-1, where FUST-1, isoform a (FUST-1A) promotes the skipping of exon 5 of its own pre-mRNA, which produces FUST-1, isoform b (FUST-1B) with different N-terminal sequences. FUST-1A is the functional isoform in circRNA regulation. Although FUST-1B has the same functional domains as FUST-1A, it cannot regulate either exon-skipping or circRNA formation. This study provided an in vivo investigation of circRNA regulation, which will be helpful to understand the mechanisms that govern circRNA formation.

scholarly journals An autoregulation loop in fust-1 for circular RNA regulation in Caenorhabditis elegans

2021 ◽  
Author(s):  
Dong Cao
Keyword(s):  
Caenorhabditis Elegans ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Exon Skipping ◽  
Circular Rna ◽  
Circular Rnas ◽  
Rna Regulation ◽  
Fused In Sarcoma ◽  
Specific Factors ◽  
Isoform B

Circular RNAs (circRNAs) are always expressed tissue-specifically, suggestive of specific factors that regulate their biogenesis. Here, taking advantage of available mutation strains of RNA binding proteins (RBPs) in Caenorhabditis elegans, I performed a screening of circRNA regulation in thirteen conserved RBPs. Among them, loss of FUST-1, the homolog of FUS (Fused in Sarcoma), caused downregulation of multiple circRNAs. By rescue experiments, I confirmed FUST-1 as a circRNA regulator. Further, I showed that FUST-1 regulates circRNA formation without affecting the levels of the cognate linear mRNAs. When recognizing circRNA pre-mRNAs, FUST-1 can affect both exon-skipping and circRNA in the same genes. Moreover, I identified an autoregulation loop in fust-1, where FUST-1, isoform a promotes the skipping of exon 5 of its own pre-mRNA, which produces FUST-1, isoform b with different N-terminal sequences. FUST-1, isoform a is the functional isoform in circRNA regulation. Although FUST-1, isoform b has the same functional domains as isoform a, it cannot regulate either exon-skipping or circRNA formation.

scholarly journals Transcriptome-wide profiles of circular RNA and RNA binding protein interactions reveal effects on circular RNA biogenesis and cancer pathway expression

2020 ◽  
Author(s):  
Trine Line Hauge Okholm ◽  
Shashank Sathe ◽  
Samuel S. Park ◽  
Andreas Bjerregaard Kamstrup ◽  
Asta Mannstaedt Rasmussen ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Protein Interactions ◽  
Binding Sites ◽  
Target Genes ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Circular Rna ◽  
Circular Rnas ◽  
Cancer Genes

AbstractCircular RNAs (circRNAs) are stable, often highly expressed RNA transcripts with potential to modulate other regulatory RNAs. A few circRNAs have been shown to bind RNA binding proteins (RBPs), however, little is known about the prevalence and strength of these interactions in different biological contexts. Here, we comprehensively evaluate the interplay between circRNAs and RBPs in the ENCODE cell lines, HepG2 and K562, by profiling the expression of circRNAs in fractionated total RNA-sequencing samples and analyzing binding sites of 150 RBPs in large eCLIP data sets. We show that KHSRP binding sites are enriched in flanking introns of circRNAs in both HepG2 and K562 cells, and that KHSRP depletion affects circRNA biogenesis. Additionally, we show that exons forming circRNAs are generally enriched with RBP binding sites compared to non-circularizing exons. To detect individual circRNAs with regulatory potency, we computationally identify circRNAs that are highly covered by RBP binding sites and experimentally validate circRNA-RBP interactions by RNA immunoprecipitations. We characterize circCDYL, a highly expressed circRNA with clinical and functional implications in bladder cancer, which is covered with GRWD1 binding sites. We confirm that circCDYL binds GRWD1 in vivo and functionally characterizes the effect of circCDYL-GRWD1 interactions on target genes in HepG2. Furthermore, we confirm interactions between circCDYL and RBPs in bladder cancer cells and demonstrate that circCDYL depletion affects hallmarks of cancer and perturbs the expression of key cancer genes, e.g. TP53 and MYC. Finally, we show that elevated levels of highly RBP-covered circRNAs, including circCDYL, are associated with overall survival of bladder cancer patients. Our study demonstrates transcriptome-wide and cell-type-specific circRNA-RBP interactions that could play important regulatory roles in tumorigenesis.

scholarly journals Identification of Novel RNA Binding Proteins Influencing Circular RNA Expression in Hepatocellular Carcinoma

2021 ◽  
Vol 22 (14) ◽  
pp. 7477
Author(s):  
Rok Razpotnik ◽  
Petra Nassib ◽  
Tanja Kunej ◽  
Damjana Rozman ◽  
Tadeja Režen
Keyword(s):  
Hepatocellular Carcinoma ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulatory Protein ◽  
Circular Rna ◽  
Differentially Expressed ◽  
Circular Rnas ◽  
Bioinformatics Analyses ◽  
Published Evidence

Circular RNAs (circRNAs) are increasingly recognized as having a role in cancer development. Their expression is modified in numerous cancers, including hepatocellular carcinoma (HCC); however, little is known about the mechanisms of their regulation. The aim of this study was to identify regulators of circRNAome expression in HCC. Using publicly available datasets, we identified RNA binding proteins (RBPs) with enriched motifs around the splice sites of differentially expressed circRNAs in HCC. We confirmed the binding of some of the candidate RBPs using ChIP-seq and eCLIP datasets in the ENCODE database. Several of the identified RBPs were found to be differentially expressed in HCC and/or correlated with the overall survival of HCC patients. According to our bioinformatics analyses and published evidence, we propose that NONO, PCPB2, PCPB1, ESRP2, and HNRNPK are candidate regulators of circRNA expression in HCC. We confirmed that the knocking down the epithelial splicing regulatory protein 2 (ESRP2), known to be involved in the maintenance of the adult liver phenotype, significantly changed the expression of candidate circRNAs in a model HCC cell line. By understanding the systemic changes in transcriptome splicing, we can identify new proteins involved in the molecular pathways leading to HCC development and progression.

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 Emerging Role and Promise of Circular RNAs in Obesity and Related Metabolic Disorders

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1473
Author(s):  
Mohamed Zaiou
Keyword(s):  
Rna Binding ◽  
Metabolic Diseases ◽  
Rna Binding Proteins ◽  
In Vivo Studies ◽  
Future Research ◽  
Circular Rnas ◽  
Exciting Field ◽  
Rna Molecules

Circular RNAs (circRNAs) are genome transcripts that are produced from back-splicing of specific regions of pre-mRNA. These single-stranded RNA molecules are widely expressed across diverse phyla and many of them are stable and evolutionary conserved between species. Growing evidence suggests that many circRNAs function as master regulators of gene expression by influencing both transcription and translation processes. Mechanistically, circRNAs are predicted to act as endogenous microRNA (miRNA) sponges, interact with functional RNA-binding proteins (RBPs), and associate with elements of the transcriptional machinery in the nucleus. Evidence is mounting that dysregulation of circRNAs is closely related to the occurrence of a range of diseases including cancer and metabolic diseases. Indeed, there are several reports implicating circRNAs in cardiovascular diseases (CVD), diabetes, hypertension, and atherosclerosis. However, there is very little research addressing the potential role of these RNA transcripts in the occurrence and development of obesity. Emerging data from in vitro and in vivo studies suggest that circRNAs are novel players in adipogenesis, white adipose browning, obesity, obesity-induced inflammation, and insulin resistance. This study explores the current state of knowledge on circRNAs regulating molecular processes associated with adipogenesis and obesity, highlights some of the challenges encountered while studying circRNAs and suggests some perspectives for future research directions in this exciting field of study.

scholarly journals The Regulatory Functions of Circular RNAs in Digestive System Cancers

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 770 ◽  
Author(s):  
Xiao Yuan ◽  
Ya Yuan ◽  
Zhi He ◽  
Diyan Li ◽  
Bo Zeng ◽  
...  
Keyword(s):  
Digestive System ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Circular Rna ◽  
Research Progress ◽  
Circular Rnas ◽  
Biological Functions ◽  
Ribonucleic Acids ◽  
Mirna Sponges ◽  
And Biological Markers

Circular ribonucleic acids (circRNAs), which are a type of covalently closed circular RNA, are receiving increasing attention. An increasing amount of evidence suggests that circRNAs are involved in the biogenesis and development of multiple diseases such as digestive system cancers. Dysregulated circRNAs have been found to act as oncogenes or tumour suppressors in digestive system cancers. Moreover, circRNAs are related to ageing and a wide variety of processes in tumour cells, such as cell apoptosis, invasion, migration, and proliferation. Moreover, circRNAs can perform a remarkable multitude of biological functions, such as regulating splicing or transcription, binding RNA-binding proteins to enable function, acting as microRNA (miRNA) sponges, and undergoing translated into proteins. However, in digestive system cancers, circRNAs function mainly as miRNA sponges. Herein, we summarise the latest research progress on biological functions of circRNAs in digestive system cancers. This review serves as a synopsis of potential therapeutic targets and biological markers for digestive system cancer.

scholarly journals Biogenesis mechanisms of circular RNA can be categorized through feature extraction of a machine learning model

2019 ◽  
Vol 35 (23) ◽  
pp. 4867-4870
Author(s):  
Chengyu Liu ◽  
Yu-Chen Liu ◽  
Hsien-Da Huang ◽  
Wei Wang
Keyword(s):  
Feature Extraction ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Cpg Island ◽  
Cpg Islands ◽  
Circular Rna ◽  
Training Data ◽  
Supplementary Information ◽  
Circular Rnas ◽  
Genomic Locus

Abstract Motivation In recent years, multiple circular RNAs (circRNA) biogenesis mechanisms have been discovered. Although each reported mechanism has been experimentally verified in different circRNAs, no single biogenesis mechanism has been proposed that can universally explain the biogenesis of all tens of thousands of discovered circRNAs. Under the hypothesis that human circRNAs can be categorized according to different biogenesis mechanisms, we designed a contextual regression model trained to predict the formation of circular RNA from a random genomic locus on human genome, with potential biogenesis factors of circular RNA as the features of the training data. Results After achieving high prediction accuracy, we found through the feature extraction technique that the examined human circRNAs can be categorized into seven subgroups, according to the presence of the following sequence features: RNA editing sites, simple repeat sequences, self-chains, RNA binding protein binding sites and CpG islands within the flanking regions of the circular RNA back-spliced junction sites. These results support all of the previously reported biogenesis mechanisms of circRNA and solidify the idea that multiple biogenesis mechanisms co-exist for different subset of human circRNAs. Furthermore, we uncover a potential new links between circRNA biogenesis and flanking CpG island. We have also identified RNA binding proteins putatively correlated with circRNA biogenesis. Availability and implementation Scripts and tutorial are available at http://wanglab.ucsd.edu/star/circRNA. This program is under GNU General Public License v3.0. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Circular RNA UBE2Q2 promotes malignant progression of gastric cancer by regulating signal transducer and activator of transcription 3-mediated autophagy and glycolysis

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Jing Yang ◽  
Xing Zhang ◽  
Jiacheng Cao ◽  
Penghui Xu ◽  
Zetian Chen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Rna Binding ◽  
Synergistic Effects ◽  
Circular Rna ◽  
Circular Rnas ◽  
In Vivo Experiments ◽  
Series Of Experiments ◽  
Transcription 3

AbstractGastric cancer remains the third leading cause of cancer-related mortality worldwide. Emerging evidence has shown that circular RNAs (circRNAs) play a critical regulatory role in the occurrence and development of various cancers through sponging miRNAs or acting as RNA-binding protein (RBP) sponges. We found that circUBE2Q2 was significantly upregulated in GC tissues and cell lines. Knockdown of circUBE2Q2 inhibited proliferation, migration, invasion, and glycolysis, and increased autophagy in vitro. In addition, knockdown of circUBE2Q2 inhibited GC tumorigenicity and metastasis potential in vivo. A series of experiments were performed to confirm that circUBE2Q2 regulates GC progression via the circUBE2Q2-miR-370-3p-STAT3 axis and promotes tumor metastasis through exosomal communication. Further in vivo experiments confirmed that, combination treatment of circUBE2Q2 knocking down and STAT3 inhibitor has synergistic effects on the gastric cancer growth inhibition, which provides a possibility to enhance the sensitivity of targeted drugs to gastric cancer through targeting circUBE2Q2. Our findings revealed that circUBE2Q2 may serve as a new proliferation-promoting factor and prognostic marker in gastric cancer.

Novel insights toward human stroke-related epigenetics: circular RNA and its impact in poststroke processes

Epigenomics ◽  
2020 ◽  
Vol 12 (22) ◽  
pp. 1957-1968
Author(s):  
Pablo W Silva ◽  
Samara M M Shimon ◽  
Leonardo M de Brito ◽  
Laís Reis-das-Mercês ◽  
Leandro Magalhães ◽  
...  
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Circular Rna ◽  
Functional Enrichment ◽  
Circular Rnas ◽  
Global Expression Profile ◽  
Human Stroke ◽  
Target Rna

Aim: Circular RNAs (circRNAs) are dysregulated in complex diseases, so we investigated their global expression profile in stroke. Material & methods: Public RNA-Seq data of human ischemic stroke lesion tissues and controls were used to perform the global expression analysis. Target RNA binding proteins and microRNAs were predicted in silico. Functional enrichment analysis was performed to infer the circRNAs’ potential roles. Results: We found that circRNAs are potentially involved in synaptic components and transmission, inflammation and ataxia. An integrative analysis revealed that hsa_circ_0078299 and FXN may be major players in the molecular stroke-context. Conclusion: Our results suggest a broad involvement of circRNAs in some stroke-related processes, indicating their potential as therapeutic targets to allow neuroprotection and brain recovery.

scholarly journals Characterizing Expression and Regulation of Gamma-Herpesviral Circular RNAs

2021 ◽  
Vol 12 ◽  
Author(s):  
Takanobu Tagawa ◽  
Daniel Oh ◽  
Jerico Santos ◽  
Sarah Dremel ◽  
Guruswamy Mahesh ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Rna Binding ◽  
De Novo ◽  
Rna Binding Proteins ◽  
Expression Patterns ◽  
Cell Types ◽  
Positive Patient ◽  
Circular Rnas ◽  
Patient Sample

Multiple herpesviruses have been recently found to encode viral circular RNAs. Like cellular circular RNAs, these RNAs lack poly-A tails and their 5′ and 3′ ends have been joined, which confers protection from RNA exonucleases. We examined the expression patterns of circular RNAs from Kaposi’s sarcoma herpesvirus (KSHV) in various environments. We performed deep sequencing of circRNA-enriched total RNA from a KSHV-positive patient lymph node for comparison with previous circRNA-Seq results. We found that circvIRF4 is highly expressed in the KSHV-positive patient sample relative to both B cell lines and de novo infected primary vascular and lymphatic endothelial cells (LECs). Overall, this patient sample showed a viral circRNA expression pattern more similar to the pattern from B cell lines, but we also discovered new back-spliced junctions and additional viral circular RNAs in this patient sample. We validated some of these back-spliced junctions as circular RNAs with standard assays. Differential expression patterns of circular RNAs in different cell types led us to investigate what cellular factors might be influencing the ratio of viral linear mRNAs to circular RNAs. We found that repression of certain RNA-binding proteins shifted the balance between viral linear mRNAs and circular RNAs. Taken together, examining viral circular RNA expression patterns may become useful tools for discovering their functions, the regulators of their expression, and determining the stage and cell types of infection in humans.

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