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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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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.
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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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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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Mapping RNA-RNA Interactions Globally Using Biotinylated Psoralen
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CAR-SPLASH identifies nascent pre-mRNA structures implicated in kinetic coupling and alternative splicing.

Hossein Shenasa1, Nova Fong1, Benjamin Erickson1

  • 1RNA Bioscience Initiative, Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045.

Proceedings of the National Academy of Sciences of the United States of America
|September 29, 2025
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Summary

Researchers discovered RNA structures, termed "RNA kinetic switches," that control pre-mRNA splicing. Disrupting these switches with antisense oligonucleotides alters alternative splicing outcomes, revealing a mechanism for kinetic coupling between transcription and splicing.

Keywords:
RNA structurealternative splicingkinetic couplingpsoralen crosslinkingtranscription elongation

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Area of Science:

  • Molecular Biology
  • RNA Biology
  • Gene Regulation

Background:

  • Pre-messenger RNA (pre-mRNA) splicing is kinetically coupled to transcription, with transcription speed influencing alternative splicing (AS) outcomes.
  • The precise molecular mechanisms underlying this kinetic coupling are not fully understood.
  • A proposed mechanism involves elongation rate-dependent alternative folding of nascent pre-mRNA.

Purpose of the Study:

  • To investigate RNA structures within nascent pre-mRNA that may mediate kinetic coupling to splicing.
  • To identify and characterize novel regulatory elements controlling alternative splicing.
  • To explore the potential of targeting these structures with antisense oligonucleotides (ASOs) for splice modulation.

Main Methods:

  • Modification of Sequencing of Psoralen Crosslinked, Ligated And Selected Hybrids (SPLASH) to Chromatin Associated RNA (CAR)-SPLASH.
  • Application of CAR-SPLASH to cells with wild-type and slow mutant RNA polymerase II.
  • Disruption of identified RNA duplexes using antisense oligonucleotides (ASOs).

Main Results:

  • Identification of over 3,000 intramolecular RNA duplexes in nascent pre-mRNA, with over 400 located near splice sites.
  • ASO-mediated disruption of specific duplexes, termed 'RNA kinetic switches,' significantly impacted alternative splicing.
  • These effects on AS of NISCH, GAK, and MEGF8 exons were dependent on transcription elongation rates.

Conclusions:

  • RNA kinetic switches mediate kinetic coupling between transcription and splicing by modulating nascent RNA structure folding.
  • Transcription speed influences RNA folding, which in turn affects alternative splicing outcomes.
  • Nascent RNA structures represent potential targets for splice-modifying ASOs.