Exitron-type splicing of intrinsically disordered regions recurs across jawed vertebrates despite sequence divergence: donor-proximal cis control in TARDBP
- 1Niigata University
Abstract
Intrinsically disordered regions (IDRs) mediate molecular interactions but can also promote aberrant self-association. Using donors embedded within IDR-coding sequences, exitron-type splicing can remove these sequences, giving them both protein-coding and splice-regulatory roles. Yet IDR amino-acid sequences often diverge rapidly, raising the question of whether and how their coding sequences support IDR-removing splicing across species. Using RNA-seq data from jawed vertebrates, we identified events predicted to remove most of an IDR while preserving annotated structured regions. Across species, donor-flanking nucleotide identity exceeded expectations from synonymous alternatives encoding the same amino-acid sequence. TARDBP, which encodes TDP-43, provided a model for examining how coding sequences both encode IDRs and regulate exitron-type splicing. Sequence-divergent vertebrate TARDBP terminal regions supported this splicing in human cells. In teleosts, TARDBP ohnologs (tardbpa and tardbpb) encoded compositionally similar disordered tails but differed markedly in IDR-removing exitron-type splicing. Reciprocal donor-proximal substitutions in zebrafish minigenes redirected donor choice and altered the balance between IDR-retaining and IDR-removing transcripts. In corresponding reporters, these substitutions altered protein-product balance and cytoplasmic puncta formation. These findings show that IDR-removing exitron-type splicing can recur despite sequence divergence and that donor-proximal TARDBP sequences both encode IDR segments and regulate IDR inclusion, linking RNA processing to protein behavior.
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BibTeX
@misc{yamagishi2026exitrontype,
title = {{Exitron-type splicing of intrinsically disordered regions recurs across jawed vertebrates despite sequence divergence: donor-proximal cis control in TARDBP}},
author = {T. Yamagishi and S. Koide and G. Toyama and A. Washida and S. Okawara and K. Yoshida and O. Onodera and A. Sugai},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.06.756961},
url = {https://www.biorxiv.org/content/10.64898/2026.10.06.756961v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Exitron-type splicing of intrinsically disordered regions recurs across jawed vertebrates despite sequence divergence: donor-proximal cis control in TARDBP
AU - T. Yamagishi
AU - S. Koide
AU - G. Toyama
AU - A. Washida
AU - S. Okawara
AU - K. Yoshida
AU - O. Onodera
AU - A. Sugai
PY - 2026
DA - 2026/10/06
PB - bioRxiv
DO - 10.64898/2026.10.06.756961
UR - https://www.biorxiv.org/content/10.64898/2026.10.06.756961v1
AB - Intrinsically disordered regions (IDRs) mediate molecular interactions but can also promote aberrant self-association. Using donors embedded within IDR-coding sequences, exitron-type splicing can remove these sequences, giving them both protein-coding and splice-regulatory roles. Yet IDR amino-acid sequences often diverge rapidly, raising the question of whether and how their coding sequences support IDR-removing splicing across species. Using RNA-seq data from jawed vertebrates, we identified events predicted to remove most of an IDR while preserving annotated structured regions. Across species, donor-flanking nucleotide identity exceeded expectations from synonymous alternatives encoding the same amino-acid sequence. TARDBP, which encodes TDP-43, provided a model for examining how coding sequences both encode IDRs and regulate exitron-type splicing. Sequence-divergent vertebrate TARDBP terminal regions supported this splicing in human cells. In teleosts, TARDBP ohnologs (tardbpa and tardbpb) encoded compositionally similar disordered tails but differed markedly in IDR-removing exitron-type splicing. Reciprocal donor-proximal substitutions in zebrafish minigenes redirected donor choice and altered the balance between IDR-retaining and IDR-removing transcripts. In corresponding reporters, these substitutions altered protein-product balance and cytoplasmic puncta formation. These findings show that IDR-removing exitron-type splicing can recur despite sequence divergence and that donor-proximal TARDBP sequences both encode IDR segments and regulate IDR inclusion, linking RNA processing to protein behavior.
ER -