室管膜瘤是大脑或脊髓的一种肿瘤。室管膜瘤的最常见和具有侵袭性的分子群是幕上ZFTA融合相关和后颅窝室管膜瘤A群。在这两个群体中，肿瘤主要发生在年幼的儿童身上，治疗后常常复发。尽管近年来已揭示了这些疾病的分子机制，但它们仍然难以针对，需要紧急创新治疗方法。在本研究中，我们使用全基因组染色体构象捕获（Hi-C）技术，结合CTCF和H3K27ac ChIP-seq、基因表达及DNA甲基化分析，鉴定与异常基因表达相关的染色体构象和调节机制。特别是，我们观察到结构变异引起的新拓扑关联区域（“新TAD”）、特异性3D染色质环以及CTCF绝缘体的DNA高甲基化替代，导致新的拓扑结构形成。通过抑制实验，我们验证了这些三维基因组构象涉及的基因在特定群体的患者来源性室管膜瘤模型中对存活的重要性。因此，本研究扩展了我们通过3D基因组构象揭示肿瘤依赖基因的能力，即使在缺乏可靶向基因突变的肿瘤中也是如此。© 2023年，作者。

Ependymoma is a tumor of the brain or spinal cord. The two most common and aggressive molecular groups of ependymoma are the supratentorial ZFTA-fusion associated and the posterior fossa ependymoma group A. In both groups, tumors occur mainly in young children and frequently recur after treatment. Although molecular mechanisms underlying these diseases have recently been uncovered, they remain difficult to target and innovative therapeutic approaches are urgently needed. Here, we use genome-wide chromosome conformation capture (Hi-C), complemented with CTCF and H3K27ac ChIP-seq, as well as gene expression and DNA methylation analysis in primary and relapsed ependymoma tumors, to identify chromosomal conformations and regulatory mechanisms associated with aberrant gene expression. In particular, we observe the formation of new topologically associating domains ('neo-TADs') caused by structural variants, group-specific 3D chromatin loops, and the replacement of CTCF insulators by DNA hyper-methylation. Through inhibition experiments, we validate that genes implicated by these 3D genome conformations are essential for the survival of patient-derived ependymoma models in a group-specific manner. Thus, this study extends our ability to reveal tumor-dependency genes by 3D genome conformations even in tumors that lack targetable genetic alterations.© 2023. The Author(s).