Enhancer-gene communication is dependent on topologically associating domains (TADs) and boundaries enforced by the CCCTC-binding factor (CTCF) insulator, but the underlying structures and mechanisms remain controversial. Here, we investigate a boundary that typically insulates fibroblast growth factor () oncogenes but is disrupted by DNA hypermethylation in gastrointestinal stromal tumors (GISTs). The boundary contains an array of CTCF sites that enforce adjacent TADs, one containing genes and the other containing and its putative enhancers, which are specifically active in GIST and its likely cell of origin. We show that coordinate disruption of four CTCF motifs in the boundary fuses the adjacent TADs, allows the enhancer to contact , and causes its robust induction. High-resolution micro-C maps reveal specific contact between transcription initiation sites in the enhancer and promoter that quantitatively scales with induction such that modest changes in contact frequency result in strong changes in expression, consistent with a causal relationship.

中文翻译：

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CTCF 拓扑边界的剖析揭示了增强子癌基因调控的原理

增强子-基因通讯依赖于拓扑关联域 (TAD) 和 CCCTC 结合因子 (CTCF) 绝缘子强制执行的边界，但潜在的结构和机制仍然存在争议。在这里，我们研究了一个通常隔离成纤维细胞生长因子 () 癌基因但在胃肠道间质瘤 (GIST) 中被 DNA 高甲基化破坏的边界。边界包含一系列执行相邻 TAD 的 CTCF 位点，一个包含基因，另一个包含其推定的增强子，这些增强子在 GIST 及其可能的起源细胞中特别活跃。我们表明，边界中四个 CTCF 基序的坐标破坏融合了相邻的 TAD，允许增强子接触 ，并导致其强大的诱导。高分辨率的 micro-C 图谱揭示了增强子和启动子中转录起始位点之间的特异性接触，这种接触随着诱导而定量缩放，从而接触频率的适度变化会导致表达的强烈变化，这与因果关系一致。