A U1-U3 snRNA-snoRNA interaction couples SF3B1 mutation to chromatin-state rewiring and genome instability
Abstract
Mutations in spliceosome factors such as SF3B1 are recurrent across human diseases, including myelodysplastic syndromes and leukemia1-4, yet splicing defects alone do not fully explain the widespread chromatin alterations and genome instability in mutant cells5. Here, by comprehensively mapping snRNA-directed RNA-RNA interactions, we identify two previously unrecognized interaction motifs in U1 snRNA beyond canonical 5' splice-site pairing6,7. These motifs enable U1 RNA to i) bind intronic and other chromatin-associated RNA (caRNA) regions outside of splice sites, and ii) base pair specifically with snoRNA. We uncover a U1-U3 snRNA-snoRNA interaction that recruits the H3K36 methyltransferase SETD2 to caRNA, promoting gene-body H3K36me3 and antagonizing H3K27me3 to modulate chromatin accessibility. The snRNA-snoRNA interface is essential for this previously unrecognized layer of chromatin and transcriptional regulation mediated through SETD2. SF3B1 mutation enhances U1-U3 binding and increases the association of the U1-U3 complex with caRNA, driving chromatin-accessibility remolding, R-loop formation, DNA damage, and copy-number abnormalities that promote tumorigenesis. A U1-specific 2'-O-methoxyethyl antisense oligonucleotide that selectively blocks U1-U3 pairing suppresses these genomic abnormalities, reduces leukemic infiltration, and prolongs survival in xenograft and patient-derived models, establishing pathological snRNA-snoRNA rewiring as a critical driver of SF3B1-mutant leukemogenesis.
Full-text reasoning
From the deep-tier full-text analysis of this preprint.
Reasoning review — 6 key claims, 6 well-supported
- supported U1 snRNA helps maintain chromatin accessibility by binding to the UACCACA motif within caRNA in intronic regions.
- supported U1 snRNA interacts with chromatin-associated RNAs (caRNA) via a novel, conserved intronic binding motif "UACCACA."
- supported U1 binding to caRNA intronic sites via the UACCACA motif contributes to PCPA suppression.
- supported A stable U1-U3 snRNA-snoRNA duplex is conserved across multiple cell types.
- supported Small nucleolar RNA (snoRNA) is a major target of snRNAs, in addition to caRNA interactions.
- supported snRNA-KARR-seq provides a framework for interrogating snRNA-directed RNA-RNA networks beyond canonical splice-site pairing.
Claims and gaps are read from the full text by a language model, shown for transparency; they do not affect ranking or selection.
Lifecycle
- biorxiv v1 2026-06-08 source ↗
Discussion
Moderated digest of third-party discussion on Bluesky — substantive endorsement and critique.
-
Aaron and the Hoskins Lab at UW Madison @uwmadisonrna.bsky.social · 595 followers neutral
Huh... some head scratching here... www.biorxiv.org/content/10.6... A U1-U3 snRNA-snoRNA interaction couples SF3B1 mutation to chromatin-state rewiring and genome instability Peng Xia, , Omar Abdel-Wahab, Bei Liu, Chuan He et al...
-
bioRxivpreprint @biorxivpreprint.bsky.social · 8893 followers neutral
A U1-U3 snRNA-snoRNA interaction couples SF3B1 mutation to chromatin-state rewiring and genome instability https://www.biorxiv.org/content/10.64898/2026.06.06.722969v1
-
bioRxiv Cell Biology @biorxiv-cellbio.bsky.social · 6027 followers neutral
A U1-U3 snRNA-snoRNA interaction couples SF3B1 mutation to chromatin-state rewiring and genome instability https://www.biorxiv.org/content/10.64898/2026.06.06.722969v1