scholarly journals Mutually exclusive splicing regulates the Nav 1.6 sodium channel function through a combinatorial mechanism that involves three distinct splicing regulatory elements and their ligands

2012 ◽  
Vol 40 (13) ◽  
pp. 6255-6269 ◽  
Author(s):  
Lorena Zubović ◽  
Marco Baralle ◽  
Francisco E. Baralle
Keyword(s):  
Sodium Channel ◽  
Regulatory Elements ◽  
Channel Function ◽  
Splicing Regulatory Elements ◽  
Combinatorial Mechanism

Homozygous SCN1B variants causing early infantile epileptic encephalopathy 52 affect voltage‐gated sodium channel function

Epilepsia ◽  
2021 ◽  
Author(s):  
Marcello Scala ◽  
Stephanie Efthymiou ◽  
Tipu Sultan ◽  
Jolien De Waele ◽  
Marta Panciroli ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Epileptic Encephalopathy ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
Channel Function

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
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