Pervasive H3K27 Acetylation Leads to ERV Expression and a Therapeutic Vulnerability in H3K27M Gliomas
普遍的H3K27乙酰化导致ERK表达和H3K27M胶质瘤中的治疗脆弱性
摘要：
High-grade gliomas defined by histone 3 K27M driver mutations exhibit global loss of H3K27 trimethylation and reciprocal gain of H3K27 acetylation, respectively shaping repressive and active chromatin landscapes.We generated tumor-derived isogenic models bearing this mutation and show that it leads to pervasive H3K27ac deposition across the genome. In turn, active enhancers and promoters are not created de novo and instead reflect the epigenomic landscape of the cell of origin. H3K27ac is enriched at repeat elements, resulting in their increased expression, which in turn can be further amplified by DNA demethylation and histone deacetylase inhibitors providing an exquisite therapeutic vulnerability. These agents may therefore modulate anti-tumor immune responses as a therapeutic modality for this untreatable disease.
由组蛋白3 K27M驱动突变定义的高级神经胶质瘤表现出H3K27三甲基化的全局性丧失和H3K27乙酰化的相互获得，分别形成抑制性和活性染色质景观。我们产生具有该突变的肿瘤衍生的同基因模型并且表明其导致普遍的H3K27ac跨基因组沉积。反过来，活跃的增强子和启动子不是从头创建的，而是反映了起源细胞的表观基因组景观。 H3K27ac富含重复元件，导致其表达增加，进而可通过DNA去甲基化和组蛋白去乙酰化酶抑制剂进一步扩增，从而提供精致的治疗脆弱性。因此，这些药剂可以调节抗肿瘤免疫应答作为这种无法治疗的疾病的治疗方式。
普遍的H3K27乙酰化导致ERK表达和H3K27M胶质瘤中的治疗脆弱性
摘要：
High-grade gliomas defined by histone 3 K27M driver mutations exhibit global loss of H3K27 trimethylation and reciprocal gain of H3K27 acetylation, respectively shaping repressive and active chromatin landscapes.We generated tumor-derived isogenic models bearing this mutation and show that it leads to pervasive H3K27ac deposition across the genome. In turn, active enhancers and promoters are not created de novo and instead reflect the epigenomic landscape of the cell of origin. H3K27ac is enriched at repeat elements, resulting in their increased expression, which in turn can be further amplified by DNA demethylation and histone deacetylase inhibitors providing an exquisite therapeutic vulnerability. These agents may therefore modulate anti-tumor immune responses as a therapeutic modality for this untreatable disease.
由组蛋白3 K27M驱动突变定义的高级神经胶质瘤表现出H3K27三甲基化的全局性丧失和H3K27乙酰化的相互获得，分别形成抑制性和活性染色质景观。我们产生具有该突变的肿瘤衍生的同基因模型并且表明其导致普遍的H3K27ac跨基因组沉积。反过来，活跃的增强子和启动子不是从头创建的，而是反映了起源细胞的表观基因组景观。 H3K27ac富含重复元件，导致其表达增加，进而可通过DNA去甲基化和组蛋白去乙酰化酶抑制剂进一步扩增，从而提供精致的治疗脆弱性。因此，这些药剂可以调节抗肿瘤免疫应答作为这种无法治疗的疾病的治疗方式。
