Mutations in IDH1 and IDH2 (encoding isocitrate dehydrogenase 1 and 2) drive the development of gliomas and other human malignancies. Mutant IDH1 induces epigenetic changes that promote tumorigenesis, but the scale and reversibility of these changes are unknown. Here, using human astrocyte and glioma tumorsphere systems, we generate a large-scale atlas of mutant-IDH1-induced epigenomic reprogramming. We characterize the reversibility of the alterations in DNA methylation, the histone landscape, and transcriptional reprogramming that occur following IDH1 mutation. We discover genome-wide coordinate changes in the localization and intensity of multiple histone marks and chromatin states. Mutant IDH1 establishes a CD24⁺ population with a proliferative advantage and stem-like transcriptional features. Strikingly, prolonged exposure to mutant IDH1 results in irreversible genomic and epigenetic alterations. Together, these observations provide unprecedented high-resolution molecular portraits of mutant-IDH1-dependent epigenomic reprogramming. These findings have substantial implications for understanding of mutant IDH function and for optimizing therapeutic approaches to targeting IDH-mutant tumors.

中文翻译：

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依赖突变体IDH1的染色质状态重编程，可逆性和持久性。

IDH1和IDH2中的突变（编码异柠檬酸脱氢酶1和2）驱动神经胶质瘤和其他人类恶性肿瘤的发展。突变IDH1诱导促进肿瘤发生的表观遗传学变化，但是这些变化的规模和可逆性尚不清楚。在这里，我们使用人类星形胶质细胞和神经胶质瘤肿瘤球系统，生成了由突变IDH1诱导的表观基因组重编程的大规模图集。我们表征了IDH1突变后发生的DNA甲基化，组蛋白景观和转录重编程变化的可逆性。我们发现全基因组坐标的变化和多个组蛋白标记和染色质状态的定位和强度。突变IDH1建立CD24 ⁺具有增殖优势和茎样转录特征的种群。令人惊讶的是，长时间暴露于突变体IDH1会导致不可逆转的基因组和表观遗传学改变。总之，这些发现为突变IDH1依赖的表观基因组重编程提供了前所未有的高分辨率分子画像。这些发现对于理解突变IDH功能和优化靶向IDH突变肿瘤的治疗方法具有重大意义。