Unannotated splicing regulatory elements in deep intron space

2021 ◽  
Author(s):  
John G. Conboy
Keyword(s):  
Regulatory Elements ◽  
Splicing Regulatory Elements

scholarly journals Functional characterization of splicing regulatory elements

2021 ◽  
Author(s):  
Scott I Adamson ◽  
Lijun Zhan ◽  
Brenton R Graveley
Keyword(s):  
High Throughput ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Functional Characterization ◽  
Regulatory Elements ◽  
Small Subset ◽  
General Sequence ◽  
Splicing Regulators ◽  
Splicing Regulatory Elements

Background: RNA binding protein-RNA interactions mediate a variety of processes including pre-mRNA splicing, translation, decay, polyadenylation and many others. Previous high-throughput studies have characterized general sequence features associated with increased and decreased splicing of certain exons, but these studies are limited by not knowing the mechanisms, and in particular, the mediating RNA binding proteins, underlying these associations. Results: Here we utilize ENCODE data from diverse data modalities to identify functional splicing regulatory elements and their associated RNA binding proteins. We identify features which make splicing events more sensitive to depletion of RNA binding proteins, as well as which RNA binding proteins act as splicing regulators sensitive to depletion. To analyze the sequence determinants underlying RBP-RNA interactions impacting splicing, we assay tens of thousands of sequence variants in a high-throughput splicing reporter called Vex-seq and confirm a small subset in their endogenous loci using CRISPR base editors. Finally, we leverage other large transcriptomic datasets to confirm the importance of RNA binding proteins which we designed experiments around and identify additional RBPs which may act as additional splicing regulators of the exons studied. Conclusions: This study identifies sequence and other features underlying splicing regulation mediated specific RNA binding proteins, as well as validates and identifies other potentially important regulators of splicing in other large transcriptomic datasets.

scholarly journals Gymnotic Delivery of LNA Mixmers Targeting Viral SREs Induces HIV-1 mRNA Degradation

2019 ◽  
Vol 20 (5) ◽  
pp. 1088 ◽  
Author(s):  
Frank Hillebrand ◽  
Philipp Ostermann ◽  
Lisa Müller ◽  
Daniel Degrandi ◽  
Steffen Erkelenz ◽  
...  
Keyword(s):  
Particle Production ◽  
Regulatory Elements ◽  
Rna Degradation ◽  
Locked Nucleic Acid ◽  
Target Sequence ◽  
Viral Particle Production ◽  
Splicing Regulatory Elements ◽  
Alternatively Spliced ◽  
Infected Cells ◽  
Hiv 1

Transcription of the HIV-1 provirus generates a viral pre-mRNA, which is alternatively spliced into more than 50 HIV-1 mRNAs encoding all viral proteins. Regulation of viral alternative splice site usage includes the presence of splicing regulatory elements (SREs) which can dramatically impact RNA expression and HIV-1 replication when mutated. Recently, we were able to show that two viral SREs, GI3-2 and ESEtat, are important players in the generation of viral vif, vpr and tat mRNAs. Furthermore, we demonstrated that masking these SREs by transfected locked nucleic acid (LNA) mixmers affect the viral splicing pattern and viral particle production. With regard to the development of future therapeutic LNA mixmer-based antiretroviral approaches, we delivered the GI3-2 and the ESEtat LNA mixmers “nakedly”, without the use of transfection reagents (gymnosis) into HIV-1 infected cells. Surprisingly, we observed that gymnotically-delivered LNA mixmers accumulated in the cytoplasm, and seemed to co-localize with GW bodies and induced degradation of mRNAs containing their LNA target sequence. The GI3-2 and the ESEtat LNA-mediated RNA degradation resulted in abrogation of viral replication in HIV-1 infected Jurkat and PM1 cells as well as in PBMCs.

scholarly journals The BRCA1 c.5434C->G (p.Pro1812Ala) variant induces a deleterious exon 23 skipping by affecting exonic splicing regulatory elements

2010 ◽  
Vol 47 (6) ◽  
pp. 398-403 ◽  
Author(s):  
P. Gaildrat ◽  
S. Krieger ◽  
J.-C. Thery ◽  
A. Killian ◽  
A. Rousselin ◽  
...  
Keyword(s):  
Regulatory Elements ◽  
Splicing Regulatory Elements

scholarly journals Evolutionary Emergence of a Novel Splice Variant with an Opposite Effect on the Cell Cycle

2015 ◽  
Vol 35 (12) ◽  
pp. 2203-2214 ◽  
Author(s):  
Muhammad Sohail ◽  
Jiuyong Xie
Keyword(s):  
Cell Cycle ◽  
Splice Variant ◽  
Splice Variants ◽  
Exon Skipping ◽  
Regulatory Elements ◽  
Cellular Processes ◽  
Human Genes ◽  
Splicing Regulatory Elements ◽  
Evolutionary Emergence ◽  
Nuclear Ribonucleoprotein

Alternative splicing contributes greatly to the diversification of mammalian proteomes, but the molecular basis for the evolutionary emergence of splice variants remains poorly understood. We have recently found a novel class of splicing regulatory elements between the polypyrimidine tract (Py) and 3′ AG (REPA) at intron ends in many human genes, including the multifunctionalPRMT5(for protein arginine methyltransferase 5) gene. The PRMT5 element is comprised of two G tracts that arise in most mammals and accompany significant exon skipping in human transcripts. The G tracts inhibit splicing by recruiting heterogeneous nuclear ribonucleoprotein (hnRNP) H and F (H/F) to reduce U2AF65 binding to the Py, causing exon skipping. The resulting novel shorter variant PRMT5S exhibits a histone H4R3 methylation effect similar to that seen with the original longer PRMT5L isoform but exhibits a distinct localization and preferential control of critical genes for cell cycle arrest at interphase in comparison to PRMT5L. This report thus provides a molecular mechanism for the evolutionary emergence of a novel splice variant with an opposite function in a fundamental cell process. The presence of REPA elements in a large group of genes implies their wider impact on different cellular processes for increased protein diversity in humans.

scholarly journals A synonymous mutation in SPINK5 exon 11 causes Netherton syndrome by altering exonic splicing regulatory elements

2012 ◽  
Vol 57 (5) ◽  
pp. 311-315 ◽  
Author(s):  
Paola Fortugno ◽  
Fabiana Grosso ◽  
Giovanna Zambruno ◽  
Serena Pastore ◽  
Flavio Faletra ◽  
...  
Keyword(s):  
Regulatory Elements ◽  
Synonymous Mutation ◽  
Netherton Syndrome ◽  
Splicing Regulatory Elements ◽  
Exon 11
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