ArticleNature communications2025
U-rich elements drive pervasive cryptic splicing in 3' UTR massively parallel reporter assays.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- NaP-TRAP: A Versatile and Accessible Workflow to Dissect Principles of Translational Regulation and mRNA Stability.Current protocols · 2026Article
- Intrinsic promoter responsiveness dictates sensitivity to transcriptional activation by enhancers.bioRxiv : the preprint server for biology · 2026Article
- Intron location and sequence modulate gene expression in Yarrowia lipolytica.Nucleic acids research · 2026Article
- NaP-TRAP: A versatile and accessible workflow to dissect principles of translational regulation and mRNA stability.bioRxiv : the preprint server for biology · 2026Article
- When RNA goes off script: ensuring transcript fidelity in transgene expression.The EMBO journal · 2026Review
- Decoding thebioRxiv : the preprint server for biology · 2026Article
- Alternative Splicing: Molecular Mechanisms, Biological Functions, Diseases, and Potential Therapeutic Targets.MedComm · 2025Review
- Massively parallel assay of human splice variants reveals cis-regulatory drivers of disease-associated and cell type-specific splicing regulation.bioRxiv : the preprint server for biology · 2025Article
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Abstract
Untranslated RNA sequences play essential roles in orchestrating gene expression. However, the sequence codes and mechanisms underpinning post-transcriptional regulation remain incompletely understood. Here, we revisit the finding from a prior massively parallel reporter assay (MPRA) that AU-rich elements in 3' untranslated regions (3' UTRs) can drive upregulation or downregulation of mRNA expression depending on 3' UTR context. We unexpectedly discover that this variable regulation arises from widespread cryptic splicing, predominately from an unannotated splice donor in the coding sequence of GFP to diverse acceptor sites in reporter 3' UTRs. Splicing is activated by U-rich sequences, which function as potent position-dependent regulators of 5' and 3' splice site choice and overall splicing efficiency. Splicing has diverse impacts on reporter expression, causing both increases and decreases in reporter expression via multiple mechanisms. We further provide evidence that cryptic splicing significantly impacts measurements made by other published 3' UTR MPRAs. Overall, our work emphasizes U-rich sequences as principal drivers of splicing and provides strategies to minimize cryptic splicing artifacts in reporter assays.
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