Glioblastoma (GBM) is the most aggressive primary brain tumor, having a poor prognosis and a median overall survival of less than two years. Over the last decade, numerous findings regarding the distinct molecular and genetic profiles of GBM have led to the emergence of several therapeutic approaches. Unfortunately, none of them has proven to be effective against GBM progression and recurrence. Epigenetic mechanisms underlying GBM tumor biology, including histone modifications, DNA methylation, and chromatin architecture, have become an attractive target for novel drug discovery strategies. Alterations on chromatin insulator elements (IEs) might lead to aberrant chromatin remodeling via DNA loop formation, causing oncogene reactivation in several types of cancer, including GBM. Importantly, it is shown that mutations affecting the isocitrate dehydrogenase (IDH) 1 and 2 genes, one of the most frequent genetic alterations in gliomas, lead to genome-wide DNA hypermethylation and the consequent IE dysfunction. The relevance of IEs has also been observed in a small population of cancer stem cells known as glioma stem cells (GSCs), which are thought to participate in GBM tumor initiation and drug resistance. Recent studies revealed that epigenomic alterations, specifically chromatin insulation and DNA loop formation, play a crucial role in establishing and maintaining the GSC transcriptional program. This review focuses on the relevance of IEs in GBM biology and their implementation as a potential theranostic target to stratify GBM patients and develop novel therapeutic approaches. We will also discuss the state-of-the-art emerging technologies using big data analysis and how they will settle the bases on future diagnosis and treatment strategies in GBM patients.

中文翻译：

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胶质母细胞瘤中的染色质隔离动力学：精准肿瘤学的挑战和未来展望

胶质母细胞瘤 (GBM) 是最具侵袭性的原发性脑肿瘤，预后较差，中位总生存期不到两年。在过去的十年中，许多关于 GBM 不同分子和遗传特征的发现导致了几种治疗方法的出现。不幸的是，它们都没有被证明对 GBM 进展和复发有效。GBM 肿瘤生物学的表观遗传机制，包括组蛋白修饰、DNA 甲基化和染色质结构，已成为新药物发现策略的有吸引力的目标。染色质绝缘体元素 (IE) 的改变可能会通过 DNA 环的形成导致异常染色质重塑，从而导致包括 GBM 在内的多种癌症中的癌基因重新激活。重要的，结果表明，影响异柠檬酸脱氢酶 (IDH) 1 和 2 基因的突变是胶质瘤中最常见的遗传改变之一，导致全基因组 DNA 高甲基化和随之而来的 IE 功能障碍。在被称为胶质瘤干细胞 (GSC) 的一小群癌症干细胞中也观察到了 IE 的相关性，这些细胞被认为参与了 GBM 肿瘤的发生和耐药性。最近的研究表明，表观基因组的改变，特别是染色质绝缘和 DNA 环的形成，在建立和维持 GSC 转录程序中起着至关重要的作用。本综述重点关注 IE 在 GBM 生物学中的相关性及其作为潜在治疗目标的实施，以对 GBM 患者进行分层并开发新的治疗方法。