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However, direct mapping of RNA\u2013RNA and DNA\u2013DNA interaction networks in complex human tissues at single-cell resolution has remained a major challenge. Here, we present SCIENCE-seq, a multimodal single-cell interactomics platform enabling simultaneous detection of RNA\u2013RNA interactions and chromatin DNA\u2013DNA contacts within individual cells. Applied to primary glioma specimens, SCIENCE-seq reveals cancer-specific interactions organized by lncRNAs and centered on key oncogenic drivers, including EGFR, hTERT, SOX2, CDK6, CDC42, CD47, and HOX loci. These datasets uncover previously unrecognized molecular relationships between premature lncRNAs and pre-mRNAs that regulate transcription, alternative splicing, and polyadenylation. Notably, we identify a glioma-specific trans-chromosomal HOX hub driven by five interacting lncRNAs. Targeting specific RNA and DNA interactions using steric antisense oligonucleotides (ASOs) or CRISPRi selectively suppresses oncogenic programs in malignant cells while sparing normal tissue, establishing chromatin interactomes as actionable therapeutic targets.<\/jats:p>","DOI":"10.64898\/2026.08.12.744478","type":"posted-content","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T23:05:11Z","timestamp":1786662311000},"source":"Crossref","is-referenced-by-count":0,"title":["Integrated single-cell profiling of RNA and DNA interactomes reveals targetable chromatin architectures in cancer"],"prefix":"10.64898","author":[{"given":"Evgeny","family":"Deforzh","sequence":"first","affiliation":[{"name":"Department of Neurology, Massachusetts General Brigham, and Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts 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