Authors
Maureen V Akinyi, Wenjie Yao, Jakub Zeman, Clara Hipp, Deniz Bartsch, Laurence Heaven, Charlotte A Le Roux, Anne C Starner, Fei Yuan, Mason D Bartels, Fangyu Zhao, Hang Le Ha, Riddhi Sharma, Bhumika Choudhary, Josep Biayna, Ralf P Brandes, Gabrijela Dumbović, Arjun Ray, Ilka Wittig, Christian Muench, Michael Sattler, Eric L Van Nostrand, Leo Kurian
Published in
bioRxiv : the preprint server for biology. Sep 07, 2025. Epub Sep 07, 2025.
Abstract
During organogenesis, precise pre-mRNA splicing is essential to assemble tissue architecture. Many developmentally essential exons bear weak 5' splice sites (5'SS) yet are spliced with high precision, implying unknown yet active splicing fidelity mechanisms. By combining transcriptome and alternative splicing profiling with temporal eCLIP mapping of RNA interactions across development, we identify the RNA-binding protein QKI as an essential direct regulator of splicing fidelity in key cardiac transcripts. Although QKI is dispensable for cardiac specification, its loss disrupts sarcomere assembly despite intact expression of sarcomere mRNAs through exon skipping and nuclear retention of mis-spliced RNAs. QKI-dependent exons in essential cardiac genes have weak 5'SS and frequently show poor complementarity with U6 snRNA. We show that QKI directly interacts with U6 snRNA using an overlapping interface to its traditional intronic binding activity, securing U4/U6·U5 tri-snRNP to ensure splicing fidelity. Thus, QKI exemplifies how context-aware RBPs enforce splicing fidelity at structurally vulnerable splice sites during organogenesis.
PMID:
40950209
Bibliographic data and abstract were imported from PubMed on 16 Oct 2026.
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