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Related Concept Videos

Alternative RNA Splicing02:18

Alternative RNA Splicing

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Alternative RNA splicing is the regulated splicing of exons and introns to produce different mature mRNAs from a single pre-mRNA. Unlike in constitutive splicing where a single gene produces a single type of mRNA, alternative splicing allows an organism to produce multiple proteins from a single gene and plays an important role in protein diversity.
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...
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Splicing is the process by which eukaryotic RNA is edited before its translation into protein. The RNA strand transcribed from eukaryotic DNA is called the primary transcript. The primary transcripts that become mRNAs are called precursor messenger RNAs (pre-mRNAs). Eukaryotic pre-mRNA contains alternating sequences of exons and introns. Exons are nucleotide sequences that code for proteins, whereas introns are the non-coding regions. In RNA splicing, introns are removed and exons are bonded...
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In eukaryotic cells, nascent mRNA transcripts need to undergo many post-transcriptional modifications to reach the cell cytoplasm and translate into functional proteins. For a long time, transcription and pre-mRNA processing were considered two independent events that occur sequentially in the cell. However, it has now been well established that transcription and pre-mRNA processing are two simultaneous processes that are precisely regulated inside the cell.
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In eukaryotic cells, transcripts made by RNA polymerase are modified and processed before exiting the nucleus. Unprocessed RNA is called precursor mRNA or pre-mRNA to distinguish it from mature mRNA.
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A gene is a stretch of DNA that serves as the blueprint for functional RNAs and proteins. Since DNA is comprised  of nucleotides and proteins are comprised of amino acids, a mediator is required to convert the information encoded in DNA into proteins. This mediator is the messenger RNA (mRNA). mRNA copies the blueprint from DNA by a process called transcription. In eukaryotes, transcription occurs in the nucleus by complementary base-pairing with the DNA template. The mRNA is then...
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Single-molecule Manipulation of G-quadruplexes by Magnetic Tweezers
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Alternative splicing modulation by G-quadruplexes.

Ilias Georgakopoulos-Soares1,2, Guillermo E Parada1,3,4,5,6, Hei Yuen Wong7

  • 1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK.

Nature Communications
|May 3, 2022
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Summary
This summary is machine-generated.

G-quadruplex (G4) motifs regulate gene splicing by influencing exon skipping and inclusion. These G4 structures are conserved across species, suggesting a fundamental role in RNA regulation.

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Area of Science:

  • Molecular Biology
  • Genetics
  • Bioinformatics

Background:

  • Alternative splicing is a key mechanism in metazoan gene regulation.
  • The precise regulatory mechanisms governing alternative splicing remain incompletely understood.
  • G-quadruplex (G4) motifs are increasingly recognized for their roles in RNA structure and function.

Purpose of the Study:

  • To investigate the enrichment and functional significance of G-quadruplex (G4) motifs in RNA splicing.
  • To determine if G4 motifs influence alternative splicing events, particularly exon skipping and inclusion.
  • To explore the evolutionary conservation and associated proteins of G4 motifs at splice sites.

Main Methods:

  • Bioinformatic analysis of RNA-seq data from human and mouse neurons to identify G4 motif enrichment near splice junctions.
  • Experimental validation of RNA G4 formation using circular dichroism spectroscopy, UV-melting, and fluorescence measurements.
  • Analysis of splice quantitative trait loci (sQTLs) and minigene experiments to assess G4s' role in splicing regulation.
  • Examination of >1,800 high-throughput experiments to identify RNA binding proteins associated with G4 motifs.
  • Cross-species analysis of G4 motif distribution at splice sites.

Main Results:

  • G-quadruplex (G4) motifs are significantly enriched (~3-fold) near splice junctions, particularly on the non-template strand.
  • G4 motifs are enriched at skipped exons in neuronal cells following depolarization.
  • Stable RNA G4 structures were experimentally validated at candidate splice sites.
  • sQTLs are enriched at G4 motifs, and minigene experiments support their role in promoting exon inclusion.
  • Multiple RNA binding proteins are associated with G4 motifs, and these motifs show conserved enrichment at splice sites in mammals and birds.

Conclusions:

  • G-quadruplex motifs play a crucial role in regulating alternative splicing, influencing both exon skipping and inclusion.
  • The enrichment and functional validation of RNA G4s highlight their importance as regulatory elements in gene expression.
  • The evolutionary conservation of G4 motifs at splice sites across mammals and birds suggests a fundamental and conserved mechanism in RNA processing.