{"id":492,"title":"Decoding the regulatory programs governing glioblastoma plasticity","title_zh":"单细胞多组学解析胶质母细胞瘤可塑性的调控程序：MYT1L 作为“守护型抑制因子”维持低可塑性状态","url":"https://doi.org/10.1038/s41586-026-11177-0","doi":"10.1038/s41586-026-11177-0","pmid":null,"journal":"Nature","kind":"paper","lang":"en","published_at":"2026-11-04T00:00:00+00:00","fetched_at":"2026-11-08T03:45:21+00:00","authors":["Manu Saraswat","Laura Rueda-Gensini","Elisa Heinzelmann","Tannia Gracia","Fani Memi","Grant de Jong","Jannes Straub","Cedar Schloo","Dirk C. Hoffmann","Erik Jung","Tim Kindinger","Louis Masclef","Bettina Weigel","Bryce Lim","Faustus Tuschmann","Sophie Weil","Oliver Gould","Richard Mair","Katharina Mikulik","Martin Rohbeck","Wolfgang Wick","Frank Winkler","Omer Ali Bayraktar","Oliver Stegle","Moritz Mall"],"primary_topic":"ethics-policy","topics":[{"slug":"ethics-policy","score":5.0,"hits":["regulation","regulatory"]},{"slug":"omics-methods","score":2.0,"hits":["multi-omic","single-cell"]}],"topic_score":5.0,"preference_score":10.0,"preference_labels":["多组学整合分析（任意生殖对象）"],"llm_score":58.0,"final_score":80.0,"score_dims":{"novelty":90,"rigor":86,"impact":35,"relevance":12,"translation":20},"recommend_reason":"方法学与机制层面质量很高：scDORI 的单细胞多组学调控网络推断及“守护型抑制因子”概念，对多组学整合分析有借鉴意义；但研究对象为胶质母细胞瘤，与生殖医学/胚胎领域几乎无直接关联，仅建议关注多组学方法学的读者浏览。","keywords":["单细胞多组学","基因调控网络","细胞可塑性","MYT1L","深度学习","胶质母细胞瘤"],"selected":1,"story_id":71,"llm_provider":"deepseek","llm_model":"deepseek-flash","llm_effort":"low","source_key":"crossref-cns","source_name":"Crossref · CNS 与大子刊新上线（领域过滤）","source_tier":1,"mention_count":1,"has_interpretation":false,"journal_key":"nature","journal_tier":"cns","journal_if":50.5,"is_mock":false,"summary_zh":"该研究提出深度学习框架 scDORI，在单细胞分辨率推断增强子驱动的基因调控网络，并应用于逾百万个原发胶质母细胞瘤细胞核的多组学（sn-multiome）图谱。结合患者来源模型的系统扰动筛选，作者发现细胞可塑性由激活因子与抑制因子不对称互作的结构化程序控制，其状态转换景观呈层级性且可预测，但存在正常神经发育中没有的跨谱系轨迹。类神经元等低可塑性状态并非稳定分化终点，而由守护型抑制因子网络主动维持；MYT1L 为其中核心成员，可结合并抑制各替代状态的主调控因子，限制可塑性并抑制体内肿瘤生长与侵袭，其缺失则重启可塑性、加速恶性表型。","summary":"Abstract Glioblastoma is incurable and resistant to therapy despite genomic stability under treatment 1–8, suggesting that non-genetic cellular plasticity is a central driver of progression. Whether such plasticity reflects stochastic state switching or is governed by predictable gene regulation has remained unclear 9–13. 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.","interpretation_basis":null,"fulltext_status":null,"interpretation":null,"fulltext":{"available":false,"status":null,"reason":"尚未抓取全文（未入选、分数未达阈值，或还没跑 fulltext 步骤）","pmcid":null,"license":null,"chars":0,"source":null,"fetched_at":null}}