{ "abstract": ". Here we introduce scDORI (single-cell deep multi-omic regulatory inference)-a deep-learning framework that infers enhancer-driven gene-regulatory networks at single-cell resolution-and apply it to single-nucleus multiome profiles of more than one million cells from primary glioblastomas. Integrating computational inference with systematic perturbation screens across patient-derived models, we show that a structured regulatory program with an asymmetric interplay of activators and repressors governs cellular plasticity in glioblastoma. The resulting transition landscape is hierarchical and predictable, but permits cross-lineage trajectories that are absent from normal neurodevelopment. Within this landscape, low-plasticity states such as the neuronal-like state are not stable differentiation end points but actively maintained configurations, stabilized by a network of safeguard repressors that silence alternative fates. We identify MYT1L as the dominant member of this network, and show that it binds to and represses master regulators of every alternative state to consolidate neuronal-like identity. MYT1L restricted plasticity even under standard-of-care therapy and suppressed tumour growth and invasion in vivo. Conversely, loss of MYT1L reactivated plasticity and accelerated malignant features, indicating that low-plasticity identity requires continuous repression. These findings reframe malignant cell state stability as a balance between activation and continuous repression, and nominate safeguard repressors as candidate therapeutic targets that are distinct from differentiation-inducing activators, with potential relevance across cancers in which phenotypic switching drives therapy resistance.", "abstract_shown": true, "affiliations": [ "Cell Fate Engineering and Disease Modeling Division, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany", "Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany", "Computational Genomics and Systems Genetics Division, German Cancer Research Center (DKFZ), Heidelberg, Germany", "European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany", "Faculty of Biosciences, Heidelberg University, Heidelberg, Germany", "HITBR Hector Institute for Translational Brain Research, Heidelberg, Germany", "Cellular Genetics Programme, Wellcome Sanger Institute, Cambridge, UK", "Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), DKFZ, Heidelberg, Germany", "Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany", "Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK", "Department of Clinical Neurosciences, Cambridge University, Cambridge, UK", "Cellular Genetics Programme, Wellcome Sanger Institute, Cambridge, UK. o.bayraktar@ucl.ac.uk", "UCL Cancer Institute, University College London, London, UK. o.bayraktar@ucl.ac.uk", "Computational Genomics and Systems Genetics Division, German Cancer Research Center (DKFZ), Heidelberg, Germany. oliver.stegle@embl.de", "European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany. oliver.stegle@embl.de", "Cell Fate Engineering and Disease Modeling Division, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany. m.mall@dkfz.de", "Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. m.mall@dkfz.de", "HITBR Hector Institute for Translational Brain Research, Heidelberg, Germany. m.mall@dkfz.de" ], "article_type": null, "arxiv": null, "author_total": 25, "authors": [ { "affs": [ 0, 1, 2, 3, 4, 5 ], "name": "Manu Saraswat", "orcid": "0000-0002-1472-8049" }, { "affs": [ 0, 1, 4, 5 ], "name": "Laura Rueda-Gensini", "orcid": "0000-0003-0138-7393" }, { "affs": [ 0, 6, 1, 4, 5 ], "name": "Elisa Heinzelmann", "orcid": "0009-0002-0160-3711" }, { "affs": [ 6 ], "name": "Tannia Gracia", "orcid": "0000-0002-8237-1870" }, { "affs": [ 6 ], "name": "Fani Memi", "orcid": "0000-0002-3685-1988" }, { "affs": [ 6 ], "name": "Grant de Jong", "orcid": "0000-0002-5614-9651" }, { "affs": [ 0, 1, 5 ], "name": "Jannes Straub", "orcid": "0000-0002-7178-1663" }, { "affs": [ 0, 1, 4, 5 ], "name": "Cedar Schloo", "orcid": "0009-0001-8531-1021" }, { "affs": [ 7, 8 ], "name": "Dirk C. Hoffmann", "orcid": "0000-0003-1370-1933" }, { "affs": [ 7, 8 ], "name": "Erik Jung", "orcid": "0000-0002-5016-8202" }, { "affs": [ 0, 1, 5 ], "name": "Tim Kindinger", "orcid": "0009-0008-4251-7522" }, { "affs": [ 0, 1, 5 ], "name": "Louis Masclef", "orcid": "0000-0003-3034-5758" }, { "affs": [ 0, 1, 4, 5 ], "name": "Bettina Weigel", "orcid": "0000-0003-1684-9087" }, { "affs": [ 0, 1, 4, 5 ], "name": "Bryce Lim", "orcid": "0000-0002-5688-3952" }, { "affs": [ 0, 1, 5 ], "name": "Faustus Tuschmann", "orcid": "0009-0006-5766-0036" }, { "affs": [ 7, 8 ], "name": "Sophie Heuer", "orcid": "0000-0002-3373-5295" }, { "affs": [ 6 ], "name": "Oliver Gould", "orcid": "0009-0009-9374-4511" }, { "affs": [ 9, 10 ], "name": "Richard James Mair", "orcid": "0000-0001-8235-5689" }, { "affs": [ 2, 4 ], "name": "Katharina Mikulik", "orcid": "0009-0006-1314-7716" }, { "affs": [ 2, 3 ], "name": "Martin Rohbeck" }, { "affs": [ 7, 8 ], "name": "Wolfgang Wick", "orcid": "0000-0002-6171-634X" }, { "affs": [ 7, 8 ], "name": "Frank Winkler", "orcid": "0000-0003-4892-6104" }, { "affs": [ 11, 12 ], "name": "Omer Ali Bayraktar", "orcid": "0000-0001-6055-277X" }, { "affs": [ 13, 14 ], "name": "Oliver Stegle", "orcid": "0000-0002-8818-7193" }, { "affs": [ 15, 16, 17 ], "name": "Moritz Mall", "orcid": "0000-0002-1278-2594" } ], "bibtex": "https://research.draconitic.com/paper/dece8xvxwd9e8.bib", "cited_by": 13, "doi": "10.1038/s41586-026-11177-0", "fulltext_url": null, "id": "dece8xvxwd9e8", "issns": [ "0028-0836", "1476-4687" ], "landing_url": "https://doi.org/10.1038/s41586-026-11177-0", "language": "en", "licence": "CC-BY", "licence_label": "CC BY", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2730|Glioma Diagnosis and Treatment" ] ], "openalex": "W4410344211", "pdf_url": "https://www.nature.com/articles/s41586-026-11177-0.pdf", "pmcid": null, "pmid": "42983099", "published": "2026-11-04", "publisher": "Nature Portfolio", "ris": "https://research.draconitic.com/paper/dece8xvxwd9e8.ris", "sources": [ { "first_seen": "2026-11-06T13:20:39Z", "native_id": "W4410344211", "source": "openalex", "url": "https://doi.org/10.1038/s41586-026-11177-0" } ], "subjects": [ { "field": "medicine", "origin": "openalex:2730|Glioma Diagnosis and Treatment", "subfield": "oncology" } ], "title": "Decoding the regulatory programs governing glioblastoma plasticity", "title_text": "Decoding the regulatory programs governing glioblastoma plasticity", "type": "peer-reviewed", "updated_at": "2026-11-09T13:21:16Z", "url": "https://research.draconitic.com/paper/dece8xvxwd9e8", "venue": "Nature", "versions": [] }