Large-scale structural analysis of pre-mRNA structure using RADIS.

Authors

Claire Fleurisson, Sijin Chen, Ryan M Macdonald, George S Stephenson, Hao Wu, Anastacia N Wienecke, Saumya Gupta, Peter J Castaldi, Ayan Paul, Kevin M Weeks, Alain Laederach

Published in

RNA (New York, N.Y.). Nov 10, 2026. Epub Nov 10, 2026.

Abstract

Pre-mRNA secondary structure can modulate the regulatory function of intronic sequences by masking or exposing splice-site signals and altering the accessibility of other features. Yet experimentally supported structural models for human pre-mRNAs have been largely restricted to splice-site-proximal sequences, leaving the deep intronic regions where ~70% of intronic disease-causing variants reside almost entirely unmapped. We developed RADIS (Reactivity Analysis of Deep and Intergenic RNA Structure), a strategy that yields strand-resolved chemical probing reactivity profiles across entire intron-rich loci by creating tiled arrays of RNAs that comprehensively span long genomic distances. This approach removes the abundance and locus-specificity constraints that otherwise limit pre-mRNA probing approaches. RADIS recovers known E. coli ribosomal RNA architectures and yields high-correlation with in-cell dimethyl sulfate (DMS)-MaP reactivities at representative splice sites (r = 0.87-0.90). RADIS-constrained folding of 109 5' and 88 3' splice sites uncovers an inverse relationship between base-pairing within the spliceosome footprint and splice-site strength, and partitions 81 branchpoints into three structural classes. Across 233 full-length Alu elements, sense Alu RNAs are more structured than antisense elements, and both partition into strand- and lineage-dependent structural classes. RADIS enables experimentally grounded structure analysis at disease-associated intronic and intergenic loci, complementing sequence-based variant-effect predictors.

PMID:
43009283
Bibliographic data and abstract were imported from PubMed on 11 Nov 2026.

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