Alternative Splicing
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2021 ◽  
Vol 22 (20) ◽  
pp. 11056
Maryam Nasiri-Aghdam ◽  
Texali C. Garcia-Garduño ◽  
Luis Felipe Jave-Suárez

Post-transcriptional modifications to coding and non-coding RNAs are unquestionably a pivotal way in which human mRNA and protein diversity can influence the different phases of a transcript’s life cycle. CELF (CUGBP Elav-like family) proteins are RBPs (RNA-binding proteins) with pleiotropic capabilities in RNA processing. Their responsibilities extend from alternative splicing and transcript editing in the nucleus to mRNA stability, and translation into the cytoplasm. In this way, CELF family members have been connected to global alterations in cancer proliferation and invasion, leading to their identification as potential tumor suppressors or even oncogenes. Notably, genetic variants, alternative splicing, phosphorylation, acetylation, subcellular distribution, competition with other RBPs, and ultimately lncRNAs, miRNAs, and circRNAs all impact CELF regulation. Discoveries have emerged about the control of CELF functions, particularly via noncoding RNAs, and CELF proteins have been identified as competing, antagonizing, and regulating agents of noncoding RNA biogenesis. On the other hand, CELFs are an intriguing example through which to broaden our understanding of the RBP/noncoding RNA regulatory axis. Balancing these complex pathways in cancer is undeniably pivotal and deserves further research. This review outlines some mechanisms of CELF protein regulation and their functional consequences in cancer physiology.

2021 ◽  
Kathrin Jansen ◽  
Noriko Shikama-Dorn ◽  
Moustafa Attar ◽  
Stefano Maio ◽  
Maria Lopopolo ◽  

Thymic epithelial cells (TEC) control the selection of a T cell repertoire reactive to pathogens but tolerant of self. This process is known to involve the promiscuous expression of virtually the entire protein-coding gene repertoire, but the extent to which TEC recapitulate peripheral isoforms, and the mechanisms by which they do so, remain largely unknown. We performed the first assembly-based transcriptomic census of transcript structures and splicing factor (SF) expression in mouse medullary TEC (mTEC) and 21 peripheral tissues. Mature mTEC expressed 60.1% of all protein-coding transcripts, more than was detected in any of the peripheral tissues. However, for genes with tissue-restricted expression, mTEC produced fewer isoforms than did the relevant peripheral tissues. Analysis of exon inclusion revealed an absence of brain-specific microexons in mTEC. We did not find unusual numbers of novel transcripts in TEC, and we show that Aire, the facilitator of promiscuous gene expression, promotes the generation of long “classical” transcripts (with 5′ and 3′ UTRs) but has only a limited impact on alternative splicing in mTEC. Comprehensive assessment of SF expression in mTEC identified a small set of nonpromiscuously expressed SF genes, among which we confirmed RBFOX to be present with AIRE in mTEC nuclei. Using a conditional loss-of-function approach, we show that Rbfox2 promotes mTEC development and regulates the alternative splicing of promiscuously expressed genes. These data indicate that TEC recommission a small number of peripheral SFs, including members of the RBFOX family, to generate a broad but selective representation of the peripheral splice isoform repertoire.

2021 ◽  
Vol 11 ◽  
Mian Liu ◽  
Rooh Afza Khushbu ◽  
Pei Chen ◽  
Hui-Yu Hu ◽  
Neng Tang ◽  

BackgroundAlternative splicing (AS) plays a key role in the diversity of proteins and is closely associated with tumorigenicity. The aim of this study was to systemically analyze RNA alternative splicing (AS) and identify its prognostic value for papillary thyroid cancer (PTC).MethodsAS percent-splice-in (PSI) data of 430 patients with PTC were downloaded from the TCGA SpliceSeq database. We successfully identified recurrence-free survival (RFS)-associated AS events through univariate Cox regression, LASSO regression and multivariate regression and then constructed different types of prognostic prediction models. Gene function enrichment analysis revealed the relevant signaling pathways involved in RFS-related AS events. Simultaneously, a regulatory network diagram of AS and splicing factors (SFs) was established.ResultsWe identified 1397 RFS-related AS events which could be used as the potential prognostic biomarkers for PTC. Based on these RFS-related AS events, we constructed a ten-AS event prognostic prediction signature that could distinguish high-and low-risk patients and was highly capable of predicting PTC patient prognosis. ROC curve analysis revealed the excellent predictive ability of the ten-AS events model, with an area under the curve (AUC) value of 0.889; the highest prediction intensity for one-year RFS was 0.923, indicating that the model could be used as a prognostic biomarker for PTC. In addition, the nomogram constructed by the risk score of the ten-AS model also showed high predictive efficiency for the prognosis of PTC patients. Finally, the constructed SF-AS network diagram revealed the regulatory role of SFs in PTC.ConclusionThrough the limited analysis, AS events could be regarded as reliable prognostic biomarkers for PTC. The splicing correlation network also provided new insight into the potential molecular mechanisms of PTC.

2021 ◽  
Wensheng Qiu

Abstract Lung adenocarcinoma (LUAD) is the leading cause of cancer deaths worldwide due to the lack of early diagnostic markers and specific drugs. Previous studies have shown the association of LUAD growth with aberrant alternative splicing (AS). Herein, clinical data of 535 tumor tissues and 59 normal tissues were extracted from the TCGA database. Each sample was analyzed using the ESTIMATE algorithm; a comparison between higher and lower score groups (stromal or immune) was made to determine the overall- and progression-free survival-related differentially expressed AS (DEAS) events. We then performed unsupervised clustering of these DEASs, followed by determining their relationship with survival rate, immune cells, and the tumor microenvironment (TME). Next, two prognostic signatures were developed using bioinformatics tools to explore the prognosis of cases with LUAD. Five OS- and six PFS-associated DEAS events were implemented to establish a prognostic risk score model. When compared to the high-risk group (HRG), the PFS and OS of the low-risk group (LRG) were found to be considerable. Additionally, a better prognosis was found considerably associated with the ESTIMATE score of the patients as well as immune cells infiltration. Our analysis of AS events in LUAD not only helps to clarify the tumorigenesis mechanism of AS, but also provides ideas for revealing potential prognostic biomarkers and therapeutic targets.

2021 ◽  
Alisha N Jones ◽  
Carina Grass ◽  
Isabel Meininger ◽  
Arie Geerlof ◽  
Melina Klostermann ◽  

Alternative splicing is controlled by differential binding of trans-acting RNA binding proteins (RBPs) to cis-regulatory elements in intronic and exonic pre-mRNA regions. How secondary structure in the pre-mRNA transcripts affects recognition by RBPs and determines alternative exon usage is poorly understood. The MALT1 paracaspase is a key component of signaling pathways that mediate innate and adaptive immune responses. Alternative splicing of MALT1 exon7 is critical for controlling optimal T cell activation. Here, we demonstrate that processing of the MALT1 pre-mRNA depends on RNA structural elements that shield the 5′ and 3′ splice sites of the alternatively spliced exon7. By combining biochemical analyses with chemical probing and NMR we show that the RBPs hnRNP U and hnRNP L bind competitively and with comparable affinities to identical stem-loop RNA structures flanking the 5′ and 3′ splice sites of MALT1 exon7. While hnRNP U stabilizes RNA stem-loop conformations that maintain exon7 skipping, hnRNP L unwinds these RNA elements to facilitate recruitment of the essential splicing factor U2AF2 to promote exon7 inclusion. Our data represent a paradigm for the control of splice site selection by differential RBP binding and modulation of pre-mRNA structure.

2021 ◽  
Vol 43 (3) ◽  
pp. 1558-1575
Yanhong Li ◽  
Jie Wang ◽  
Mauricio A. Elzo ◽  
Huimei Fan ◽  
Kun Du ◽  

DNA methylation and the alternative splicing of precursor messenger RNAs (pre-mRNAs) are two important genetic modification mechanisms. However, both are currently uncharacterized in the muscle metabolism of rabbits. Thus, we constructed the Tianfu black rabbit obesity model (obese rabbits fed with a 10% high-fat diet and control rabbits from 35 days to 70 days) and collected the skeletal muscle samples from the two groups for Genome methylation sequencing and RNA sequencing. DNA methylation data showed that the promoter regions of 599 genes and gene body region of 2522 genes had significantly differential methylation rates between the two groups, of which 288 genes had differential methylation rates in promoter and gene body regions. Analysis of alternative splicing showed 555 genes involved in exon skipping (ES) patterns, and 15 genes existed in differential methylation regions. Network analysis showed that 20 hub genes were associated with ubiquitinated protein degradation, muscle development pathways, and skeletal muscle energy metabolism. Our findings suggest that the two types of genetic modification have potential regulatory effects on skeletal muscle development and provide a basis for further mechanistic studies in the rabbit.

2021 ◽  
Vol 12 ◽  
Wensheng Liu ◽  
Yinan Zhao ◽  
Xiaohua Liu ◽  
Xiaoya Zhang ◽  
Jiancheng Ding ◽  

Spermatocyte meiosis is the cornerstone of mammalian production. Thousands of long noncoding RNAs (lncRNAs) have been reported to be functional in various cellular processes, but the function of lncRNAs in meiosis remains largely unknown. Here, we profiled lncRNAs in spermatocytes at stage I of meiosis and identified a testis-specific lncRNA, Rbakdn, as a vital regulator of meiosis. Rbakdn is dynamically expressed during meiosis I, and Rbakdn knockdown inhibits meiosis in vitro. Furthermore, Rbakdn knockdown in testes in mice by intratesticular injection disturbs meiosis, reduces testicular volume, and increases apoptosis of spermatocytes, resulting in vacuolation of the seminiferous tubules. Rbakdn can bind to Ptbp2, an RNA-binding protein that is important in the regulation of the alternative splicing of many genes in spermatogenesis. Rbakdn knockdown leads to a decrease in Ptbp2 through the ubiquitination degradation pathway, indicating that Rbakdn maintains the stability of Ptbp2. In conclusion, our study identified an lncRNA, Rbakdn, with a crucial role in meiosis.

2021 ◽  
Vol 22 ◽  
Kevin Regan ◽  
Abolfazl Saghafi ◽  
Zhijun Li

Background: Splice junctions are the key to going from pre-messenger RNA to mature messenger RNA in many multi-exon genes due to alternative splicing. Since the percentage of multi-exon genes that undergo alternative splicing is very high, identifying splice junctions is an attractive research topic with important implications. Objective: The aim is to develop a deep learning model capable of identifying splice junctions in RNA sequences using 13,666 unique sequences of primate RNA. Method: A Long Short-Term Memory (LSTM) Neural Network model is developed that classifies a given sequence as EI (Exon-Intron splice), IE (Intron-Exon splice), or N (No splice). The model is trained with groups of trinucleotides and its performance is tested using validation and test data to prevent bias. Results: Model performance was measured using accuracy and f-score in test data. The finalized model achieved an average accuracy of 91.34% with an average f-score of 91.36% over 50 runs. Conclusion: Comparisons show a highly competitive model to recent Convolutional Neural Network structures. The proposed LSTM model achieves the highest accuracy and f-score among published alternative LSTM structures.

Héctor Apablaza ◽  
Myriam Solís ◽  
Daniel Conejera ◽  
Alexis Fonseca ◽  
Jorge Cid ◽  

Tao Zhang ◽  
Sixia Chen ◽  
Yi Peng ◽  
Changgang Wang ◽  
Xi Cheng ◽  

Background: Gene expression and alternative splicing (AS) can promote cancer development via complex mechanisms. We aimed to identify and verify the hub AS events and splicing factors associated with the progression of colorectal cancer (CRC).Methods: RNA-Seq data, clinical data, and AS events of 590 CRC samples were obtained from the TCGA and TCGASpliceSeq databases. Cox univariable and multivariable analyses, KEGG, and GO pathway analyses were performed to identify hub AS events and splicing factor/spliceosome genes, which were further validated in five CRCs.Results: In this study, we first compared differentially expressed genes and gene AS events between normal and tumor tissues. Differentially expressed genes were different from genes with differentially expressed AS events. Prognostic analysis and co-expression network analysis of gene expression and gene AS events were conducted to screen five hub gene AS events involved in CRC progression: EPB41L2, CELF2, TMEM130, VCL, and SORBS2. Using qRT-PCR, we also verified that the gene AS events SORBS2 were downregulated in tumor tissue, and gene AS events EPB41L2, CELF2, TMEM130, and VCL were upregulated in tumor tissue. The genes whose mRNA levels were significantly related to the five hub gene AS events were significantly enriched in the GO term of cell division and Notch signaling pathway. Further coexpression of gene AS events and alternative splicing factor genes revealed NOVA1 as a crucial factor regulating the hub gene AS event expression in CRC. Through in vitro experiments, we found that NOVA1 inhibited gene AS event SORBS2, which induced the migration of CRC cells via the Notch pathway.Conclusion: Integrated analysis of gene expression and gene AS events and further experiments revealed that NOVA1-mediated SORBS2 promoted the migration of CRC, indicating its potential as a therapeutic target.

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