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Poison Exon Splicing Regulates a Coordinated Network of SR Protein Expression during Differentiation and

Nathan K Leclair1, Mattia Brugiolo2, Laura Urbanski1

  • 1The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA; Graduate Program in Genetics and Development, UConn Health, Farmington, CT, USA.

Molecular Cell
|November 11, 2020
PubMed

Insights

Altered splicing factor (SF) expression impacts disease. This study reveals how poison exons in SFs are regulated, uncovering a network controlling SF expression and demonstrating therapeutic potential for breast cancer by targeting TRA2β-PE splicing.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Splicing factors (SFs) regulate RNA isoforms, and their dysregulation is linked to diseases.
  • Poison exons (PEs) within SFs are highly conserved but their function and regulation are unclear.

Purpose of the Study:

  • To investigate the regulation and physiological role of PEs in serine-arginine-rich (SR) proteins.
  • To identify regulatory elements controlling PE splicing and protein expression of the oncogenic SF TRA2β.
  • To explore therapeutic strategies for reversing aberrant PE splicing in cancer.

Main Methods:

  • Analysis of PE splicing during induced pluripotent stem cell (iPSC) differentiation and in tumor tissues.
  • RNA-targeting CRISPR screens to identify regulatory sequences for TRA2β-PE.
  • CRISPR artificial SFs to assess RS domain activity.
  • Development of splice-switching antisense oligonucleotides (ASOs).

Main Results:

  • PEs in SR proteins are differentially spliced in iPSCs and tumors.
  • An extensive cross-regulatory network of SR proteins controlling alternative splicing and nonsense-mediated decay was uncovered.
  • Specific sequences regulating TRA2β-PE inclusion and protein levels were identified.
  • ASOs targeting TRA2β-PE reversed aberrant splicing in breast cancer cells, impacting viability, proliferation, and migration.

Conclusions:

  • PEs in SR proteins are dynamically regulated and play roles in development and disease.
  • A complex regulatory network involving SR proteins and alternative splicing governs SF expression.
  • Targeting TRA2β-PE splicing with ASOs shows promise for breast cancer therapy.
Keywords:
RNA splicing, SR proteins, differentiation, cancer, cross-regulation, antisense oligonucleotides, CRISPR/Cas13, CRISPR-Artificial Splicing Factors, alternative splicing, oncogene

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