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Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
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Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells

Published on: April 26, 2017

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Specific inhibition of splicing factor activity by decoy RNA oligonucleotides

Polina Denichenko1, Maxim Mogilevsky1, Antoine Cléry2

  • 1Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, 9112001, Israel.

Nature Communications
|April 10, 2019
PubMed

Insights

Researchers developed novel decoy oligonucleotides to inhibit aberrant splicing factor (SF) activity in diseases. These targeted molecules offer a new therapeutic strategy for conditions involving dysregulated gene expression.

Area of Science:

  • Molecular Biology
  • Gene Expression Regulation
  • RNA Biology

Background:

  • Alternative splicing is crucial for gene expression and its dysregulation is implicated in various diseases, including cancer.
  • Splicing factors (SFs) control alternative splicing but lack direct inhibitors, despite their altered activity in disease states.

Purpose of the Study:

  • To design and validate decoy oligonucleotides as a novel approach to inhibit specific splicing factor activity.
  • To investigate the potential of these decoys to downregulate SFs in disease contexts characterized by their hyperactivity.

Main Methods:

  • Designed decoy oligonucleotides containing repeated RNA motifs recognized by specific SFs.
  • Tested the binding affinity and inhibitory capacity of decoy oligonucleotides against RBFOX1/2, SRSF1, and PTBP1.
  • Evaluated the efficacy of decoy oligonucleotides in vitro and in vivo.

Main Results:

  • Decoy oligonucleotides specifically bound to their targeted splicing factors (RBFOX1/2, SRSF1, PTBP1).
  • These decoys successfully inhibited the splicing and biological activities of the targeted SFs.
  • Inhibition was demonstrated both in vitro and in vivo, confirming the decoys' effectiveness.

Conclusions:

  • Decoy oligonucleotides represent a promising strategy for specifically downregulating aberrant splicing factor activity.
  • This approach offers a potential therapeutic avenue for diseases driven by up-regulated or hyperactive splicing factors.

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