Specificity and exon target space of splicing modifying compounds.

Area of Science:

• Molecular Biology
• Genetics
• Drug Discovery

Background:

• RNA splicing modulation is a therapeutic strategy influencing gene expression.
• Small-molecule splicing modifiers like Risdiplam and Branaplam induce exon inclusion.
• Current understanding of splicing modifier specificity is limited, with many predicted targets unresponsive.

Purpose of the Study:

• To investigate the molecular basis of splicing-modulator specificity.
• To identify sequence-dependent features governing exon responsiveness to splicing modifiers.
• To explore reprogramming splicing modifier specificity through U1 snRNA manipulation.

Main Methods:

• Biochemical assays
• Transcriptome analyses
• Genetic perturbations

Main Results:

• Identified sequence-dependent features that determine exon responsiveness to splicing-modulator induction.
• Demonstrated that splicing modifier specificity can be reprogrammed by manipulating U1 snRNA.
• Refined the understanding of determinants for splicing-modulator target space.

Conclusions:

• Sequence features play a critical role in determining splicing-modulator specificity.
• U1 snRNA manipulation offers a strategy to reprogram splicing modifier specificity.
• Findings may facilitate the identification of novel target exons and therapeutic compounds.