Mutations in spliceosome factors such as SF3B1 are recurrent across human diseases, including myelodysplastic syndromes and leukemia, yet splicing defects alone do not fully explain the widespread chromatin alterations and genome instability in mutant cells. Here, by comprehensively mapping snRNA directed RNA-RNA interactions, we identify two previously unrecognized interaction motifs in U1 snRNA beyond canonical splice site pairing. 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 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.
Xia, P., Li, H., Ji, Y., Ju, C.-w., Pan, Y., Mo, J., Zhu, X., Zhao, L., Lyu, R., Niewold, E., Fernandez, M., Ai, Y., Wei, J., Bradley, R. K., Wang, L., Abdel-Wahab, O., Liu, B., He, C.
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