{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:27:13Z","timestamp":1785414433060,"version":"3.56.0"},"posted":{"date-parts":[[2026,6,8]]},"group-title":"Cell Biology","reference-count":49,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"id":[{"id":"https:\/\/ror.org\/006w34k90","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/02qwkrw10","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Mutations in spliceosome factors such as SF3B1 are recurrent across human diseases, including myelodysplastic syndromes and leukemia\n                  <jats:sup>1\u20134<\/jats:sup>\n                  , yet splicing defects alone do not fully explain the widespread chromatin alterations and genome instability in mutant cells\n                  <jats:sup>5<\/jats:sup>\n                  . Here, by comprehensively mapping snRNA-directed RNA\u2013RNA interactions, we identify two previously unrecognized interaction motifs in U1 snRNA beyond canonical 5\u2032 splice-site pairing\n                  <jats:sup>6,7<\/jats:sup>\n                  . 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\u2013U3 snRNA\u2013snoRNA interaction that recruits the H3K36 methyltransferase SETD2 to caRNA, promoting gene-body H3K36me3 and antagonizing H3K27me3 to modulate chromatin accessibility. The snRNA\u2013snoRNA interface is essential for this previously unrecognized layer of chromatin and transcriptional regulation mediated through SETD2. SF3B1 mutation enhances U1\u2013U3 binding and increases the association of the U1\u2013U3 complex with caRNA, driving chromatin-accessibility remolding, R-loop formation, DNA damage, and copy-number abnormalities that promote tumorigenesis. A U1-specific 2\u2032-O-methoxyethyl antisense oligonucleotide that selectively blocks U1\u2013U3 pairing suppresses these genomic abnormalities, reduces leukemic infiltration, and prolongs survival in xenograft and patient-derived models, establishing pathological snRNA\u2013snoRNA rewiring as a critical driver of SF3B1-mutant leukemogenesis.\n                <\/jats:p>","DOI":"10.64898\/2026.06.06.722969","type":"posted-content","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T21:30:19Z","timestamp":1780954219000},"source":"Crossref","is-referenced-by-count":0,"title":["A U1\u2013U3 snRNA\u2013snoRNA interaction couples SF3B1 mutation to chromatin-state rewiring and genome instability"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6046-3790","authenticated-orcid":false,"given":"Peng","family":"Xia","sequence":"first","affiliation":[{"name":"Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA"},{"name":"Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA"},{"name":"Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA"},{"name":"Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA"},{"name":"Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiyi","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA"},{"name":"Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA"},{"name":"Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-wei","family":"Ju","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA"},{"name":"Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA"},{"name":"Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiqian","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA"},{"name":"Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA"},{"name":"Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Mo","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The 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