The occurrence and formation of genomic structural variants (SVs) is known to be influenced by the 3D chromatin architecture, but the extent and magnitude have been challenging to study. Here, we apply Hi-C to study chromatin organization before and after induction of chromothripsis in human cells. We use Hi-C to manually assemble the derivative chromosomes following the occurrence of massive complex rearrangements, which allows us to study the sources of SV formation and their consequences on gene regulation. We observe an action–reaction interplay whereby the 3D chromatin architecture directly impacts the location and formation of SVs. In turn, the SVs reshape the chromatin organization to alter the local topologies, replication timing, and gene regulation in cis. We show that SVs have a strong tendency to occur between similar chromatin compartments and replication timing regions. Moreover, we find that SVs frequently occur at 3D loop anchors, that SVs can cause a switch in chromatin compartments and replication timing, and that this is a major source of SV-mediated effects on nearby gene expression changes. Finally, we provide evidence for a general mechanistic bias of the 3D chromatin on SV occurrence using data from more than 2700 patient-derived cancer genomes.

中文翻译：

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体细胞结构变异的形成由基因组结构引导并影响基因组结构

已知基因组结构变异 (SV) 的发生和形成受 3D 染色质结构的影响，但其程度和程度一直难以研究。在这里，我们应用 Hi-C 研究在人类细胞中诱导染色体碎裂之前和之后的染色质组织。我们使用 Hi-C 在发生大规模复杂重排后手动组装衍生染色体，这使我们能够研究 SV 形成的来源及其对基因调控的影响。我们观察到动作-反应相互作用，其中 3D 染色质结构直接影响 SV 的位置和形成。反过来，SVs 重塑染色质组织以改变 cis 中的局部拓扑结构、复制时间和基因调控. 我们表明 SV 在相似的染色质区室和复制时间区域之间具有很强的发生趋势。此外，我们发现 SV 经常出现在 3D 循环锚点处，SV 可以导致染色质区室和复制时间的转换，这是 SV 介导的对附近基因表达变化的影响的主要来源。最后，我们使用来自 2700 多个患者来源的癌症基因组的数据，为 3D 染色质对 SV 发生的一般机制偏差提供了证据。