scholarly journals Intragenic recruitment of NF-κB drives alternative splicing modifications upon activation by the viral oncogene TAX of HTLV-1

2019 ◽  
Author(s):  
Lamya Ben Ameur ◽  
Morgan Thenoz ◽  
Guillaume Giraud ◽  
Emmanuel Combe ◽  
Jean-Baptiste Claude ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Rna Splicing ◽  
Major Part ◽  
Splicing Regulation ◽  
Dependent Manner ◽  
Gene Promoters ◽  
Helicase Activity ◽  
Viral Oncogene ◽  
Oncogenic Pathways ◽  
Splicing Regulator

SummaryThe chronic NF-κB activation in inflammation and cancer has long been linked to persistent activation of NF-κB responsive gene promoters. However, NF-κB factors such as RELA also massively bind to gene bodies. Here, we demonstrate that the recruitment of RELA to intragenic regions regulates alternative splicing upon activation of NF-κB by the viral oncogene TAX of HTLV-1. Integrative analysis of RNA splicing and chromatin occupancy, combined with chromatin tethering assays, demonstrate that DNA-bound RELA interacts with and recruits the splicing regulator DDX17 in a NF-kB activation-dependent manner, leading to alternative splicing of target exons thanks to DDX17 RNA helicase activity. This NF-kB/DDX17 axis accounts for a major part of the TAX-induced alternative splicing landscape that mainly affects genes involved in oncogenic pathways. Collectively, our results demonstrate a physical and direct involvement of NF-κB in alternative splicing regulation, which significantly revisits our knowledge of HTLV-1 pathogenesis and other NF-κB-related diseases.

scholarly journals Regulation of CD44 Alternative Splicing by SRm160 and Its Potential Role in Tumor Cell Invasion

2006 ◽  
Vol 26 (1) ◽  
pp. 362-370 ◽  
Author(s):  
Chonghui Cheng ◽  
Phillip A. Sharp
Keyword(s):  
Alternative Splicing ◽  
Tumor Cell ◽  
Cell Invasion ◽  
Rna Splicing ◽  
Tumor Cell Invasion ◽  
Dependent Manner ◽  
Cd44 Isoforms ◽  
Transmembrane Glycoprotein ◽  
Cell Invasiveness ◽  
Interfering Rna

ABSTRACT The multiple isoforms of the transmembrane glycoprotein CD44 are produced by alternative RNA splicing. Expression of CD44 isoforms containing variable 5 exon (v5) correlates with enhanced malignancy and invasiveness of some tumors. Here we demonstrate that SRm160, a splicing coactivator, regulates CD44 alternative splicing in a Ras-dependent manner. Overexpression of SRm160 stimulates inclusion of CD44 v5 when Ras is activated. Conversely, small interfering RNA (siRNA)-mediated silencing of SRm160 significantly reduces v5 inclusion. Immunoprecipitation shows association of SRm160 with Sam68, a protein that also stimulates v5 inclusion in a Ras-dependent manner, suggesting that these two proteins interact to regulate CD44 splicing. Importantly, siRNA-mediated depletion of CD44 v5 decreases tumor cell invasion. Reduction of SRm160 by siRNA transfection downregulates the endogenous levels of CD44 isoforms, including v5, and correlates with a decrease in tumor cell invasiveness.

scholarly journals The U1 snRNP subunit LUC7 controls plant development and stress response through alternative splicing regulation

2017 ◽  
Author(s):  
Marcella de Francisco Amorim ◽  
Eva-Maria Willing ◽  
Anchilie G. Francisco-Mangilet ◽  
Irina Droste-Borel ◽  
Boris Maček ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Plant Development ◽  
Nuclear Export ◽  
Macromolecular Complex ◽  
Splicing Regulation ◽  
Dependent Manner ◽  
Accessory Factor ◽  
U1 Snrnp ◽  
Member Gene ◽  
Rna Immunoprecipitation

AbstractIntrons are removed by the spliceosome, a large macromolecular complex composed of five ribonucleoprotein subcomplexes (U snRNP). The U1 snRNP, which binds to 5’ splice sites, plays an essential role in early steps of the splicing reaction. Here, we show that Arabidopsis LUC7 proteins, which are encoded by a three-member gene family in Arabidopsis, are important for plant development and stress resistance. We show that LUC7 are U1 snRNP accessory proteins by RNA immunoprecipitation experiments and LUC7 protein complex purifications. Transcriptome analyses revealed that LUC7 proteins are not only important for constitutive splicing, but also affects hundreds of alternative splicing events. Interestingly, LUC7 proteins specifically promote splicing of a subset of terminal introns. Splicing of LUC7-dependent introns is a prerequisite for nuclear export and some splicing events are modulated by stress in a LUC7-dependent manner. Taken together our results highlight the importance of the U1 snRNP component LUC7 in splicing regulation and suggest a previously unrecognized role of a U1 snRNP accessory factor in terminal intron splicing.

Abstract 15: Global RNA Splicing Regulation in Cardiac Maturation

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Chen Gao ◽  
Shuxun Ren ◽  
Jae-Hyung Lee ◽  
Yun-Hua Esther Hsiao ◽  
Xinshu (Grace) Xiao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Rna Sequencing ◽  
Rna Splicing ◽  
Mrna Splicing ◽  
Splicing Regulation ◽  
Sequencing Analysis ◽  
Cell Based Therapy ◽  
Alternative Mrna Splicing ◽  
Cardiac Maturation

Background: The complexity of transcriptome and proteome is contributed by alternative splicing of mRNA. Altered mRNA splicing is implicated in both development and disease. However, the change of alternative mRNA splicing during cardiomyocytes maturation is unknown, and the regulatory mechanisms remain unexplored. Methods and Results: Using deep RNA-Sequencing, we identified global alternative splicing changes associated with both cardiac development and pathological remodeling in mouse heart. Further, we identified a highly conserved splicing regulator-RBFox1 to be significantly induced during zebrafish, mouse and human cardiac maturation. RBFox1 expression was also detected in cardiomyocytes derived from both mouse and human embryonic stem cells but at much lower levels comparing to adult heart. In zebrafish embryos, inactivation of RBFox1 caused cardiomyocyte maturation defects. Expression of RBFox1 in cultured neonatal cardiomyocytes was sufficient to promote maturation by reducing fetal marker gene expression while increasing calcium handling gene expression including RyR and promoting sarcomere organization. Deep RNA-Sequencing analysis showed that RBFox1 expression promoted alternative splicing in genes involved in calcium cycling, blood vessel development and muscle contraction. Finally, we identified a highly conserved mutually exclusive alternative splicing event of transcription factor MEF2 to be a direct downstream target of RBFox1. Expression of individual MEF2 splicing variants led to different cardiac developmental phenotypes in zebrafish, indicating their different transcriptional activities. Conclusion: Our study provided the first comprehensive analysis of mRNA splicing regulation in heart during post-natal development and heart failure, and identified RBFox1 as a key regulator for alternative RNA splicing during cardiomyocytes maturation. Further exploration of RBFox1 mediated RNA splicing regulation in heart may yield novel insight to the underlying mechanisms of cardiac maturation and new approach to improve cell based therapy for heart diseases.

scholarly journals RNA Binding Protein Ptbp2 Is Essential for Male Germ Cell Development

2015 ◽  
Vol 35 (23) ◽  
pp. 4030-4042 ◽  
Author(s):  
Leah L. Zagore ◽  
Sarah E. Grabinski ◽  
Thomas J. Sweet ◽  
Molly M. Hannigan ◽  
R. Michael Sramkoski ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Germ Cell ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Cell Loss ◽  
Cell Development ◽  
Splicing Regulation ◽  
Germ Cell Development ◽  
Splicing Regulator ◽  
Alternatively Spliced

RNA binding proteins (RBPs) are increasingly recognized as essential factors in tissue development and homeostasis. The polypyrimidine tract binding (PTB) protein family of RBPs are important posttranscriptional regulators of gene expression. In the nervous system, the function and importance of PTB protein 2 (Ptbp2) as a key alternative splicing regulator is well established. Ptbp2 is also abundantly expressed during spermatogenesis, but its role in this developmental program has not been explored. Additionally, the importance of alternative splicing regulation in spermatogenesis is unclear. Here, we demonstrate that Ptbp2 is essential for spermatogenesis. We also describe an improved dual fluorescence flow cytometry strategy to discriminate, quantify, and collect germ cells in different stages of development. Using this approach, in combination with traditional histological methods, we show that Ptbp2 ablation results in germ cell loss due to increased apoptosis of meiotic spermatocytes and postmeiotic arrest of spermatid differentiation. Furthermore, we show that Ptbp2 is required for alternative splicing regulation in the testis, as in brain. Strikingly, not all of the alternatively spliced RNAs examined were sensitive to Ptbp2 loss in both tissues. Collectively, the data provide evidence for an important role for alternative splicing regulation in germ cell development and a central role for Ptbp2 in this process.

scholarly journals Alternative RNA splicing regulation in the testis

Reproduction ◽  
2006 ◽  
Vol 132 (6) ◽  
pp. 811-819 ◽  
Author(s):  
David J Elliott ◽  
Sushma N Grellscheid
Keyword(s):  
Alternative Splicing ◽  
Binding Sites ◽  
Rna Splicing ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Developmental Pathways ◽  
Splicing Regulation ◽  
Sequence Elements ◽  
Cell Type Specific ◽  
Developmental Programme

Alternative splicing regulation has been shown to be critically important for several developmental pathways. It is particularly prevalent in the testis, which is the site of an extensive adult developmental programme. Alternative splicing is controlled by a splicing code, in which transcripts respond to subtle cell type-specific variations in positive and negative trans-acting RNA-binding proteins according to their unique set of binding sites for these proteins. Because of their unique combinations ofcis-acting sequence elements, specific transcripts are able to respond individually to this code. In this review, we discuss how this code may be deciphered in germ cells to mediate a splicing response.

scholarly journals Role of Alternative Splicing in Regulating Host Response to Viral Infection

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1720
Author(s):  
Kuo-Chieh Liao ◽  
Mariano A. Garcia-Blanco
Keyword(s):  
Innate Immunity ◽  
Alternative Splicing ◽  
Immune Responses ◽  
Viral Infection ◽  
Rna Splicing ◽  
Type I ◽  
Host Immune Responses ◽  
Transcriptional Regulatory Mechanisms ◽  
Host Virus Interactions

The importance of transcriptional regulation of host genes in innate immunity against viral infection has been widely recognized. More recently, post-transcriptional regulatory mechanisms have gained appreciation as an additional and important layer of regulation to fine-tune host immune responses. Here, we review the functional significance of alternative splicing in innate immune responses to viral infection. We describe how several central components of the Type I and III interferon pathways encode spliced isoforms to regulate IFN activation and function. Additionally, the functional roles of splicing factors and modulators in antiviral immunity are discussed. Lastly, we discuss how cell death pathways are regulated by alternative splicing as well as the potential role of this regulation on host immunity and viral infection. Altogether, these studies highlight the importance of RNA splicing in regulating host–virus interactions and suggest a role in downregulating antiviral innate immunity; this may be critical to prevent pathological inflammation.

U2AF - Hypoxia-induced fas alternative splicing regulator

2021 ◽  
Vol 399 (1) ◽  
pp. 112444
Author(s):  
Laurynas Vilys ◽  
Inga Peciuliene ◽  
Egle Jakubauskiene ◽  
Ruta Zinkeviciute ◽  
Yuichi Makino ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Splicing Regulator

scholarly journals Profiling PRMT methylome reveals roles of hnRNPA1 arginine methylation in RNA splicing and cell growth

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wen-juan Li ◽  
Yao-hui He ◽  
Jing-jing Yang ◽  
Guo-sheng Hu ◽  
Yi-an Lin ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Cell Growth ◽  
Rna Splicing ◽  
Synergistic Effects ◽  
Arginine Methylation ◽  
Type I ◽  
Prostate Cancer Cells ◽  
Cancer Cell Growth ◽  
Cancer Mutations ◽  
Substrate Spectrum

AbstractNumerous substrates have been identified for Type I and II arginine methyltransferases (PRMTs). However, the full substrate spectrum of the only type III PRMT, PRMT7, and its connection to type I and II PRMT substrates remains unknown. Here, we use mass spectrometry to reveal features of PRMT7-regulated methylation. We find that PRMT7 predominantly methylates a glycine and arginine motif; multiple PRMT7-regulated arginine methylation sites are close to phosphorylations sites; methylation sites and proximal sequences are vulnerable to cancer mutations; and methylation is enriched in proteins associated with spliceosome and RNA-related pathways. We show that PRMT4/5/7-mediated arginine methylation regulates hnRNPA1 binding to RNA and several alternative splicing events. In breast, colorectal and prostate cancer cells, PRMT4/5/7 are upregulated and associated with high levels of hnRNPA1 arginine methylation and aberrant alternative splicing. Pharmacological inhibition of PRMT4/5/7 suppresses cancer cell growth and their co-inhibition shows synergistic effects, suggesting them as targets for cancer therapy.

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