Differences in three-dimensional (3D) chromatin architecture can influence the integrity of topologically associating domains (TADs) and rewire specific enhancer-promoter interactions, impacting gene expression and leading to human disease. Here we investigate the 3D chromatin architecture in T cell acute lymphoblastic leukemia (T-ALL) by using primary human leukemia specimens and examine the dynamic responses of this architecture to pharmacological agents. Systematic integration of matched in situ Hi-C, RNA-seq and CTCF ChIP-seq datasets revealed widespread differences in intra-TAD chromatin interactions and TAD boundary insulation in T-ALL. Our studies identify and focus on a TAD 'fusion' event associated with absence of CTCF-mediated insulation, enabling direct interactions between the MYC promoter and a distal super-enhancer. Moreover, our data also demonstrate that small-molecule inhibitors targeting either oncogenic signal transduction or epigenetic regulation can alter specific 3D interactions found in leukemia. Overall, our study highlights the impact, complexity and dynamic nature of 3D chromatin architecture in human acute leukemia.

中文翻译：

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T细胞急性淋巴细胞白血病的三维染色质景观。

三维 (3D) 染色质结构的差异会影响拓扑关联域 (TAD) 的完整性，并重新连接特定的增强子-启动子相互作用，影响基因表达并导致人类疾病。在这里，我们通过使用原发性人类白血病标本研究 T 细胞急性淋巴细胞白血病 (T-ALL) 中的 3D 染色质结构，并检查这种结构对药物的动态反应。匹配的原位 Hi-C、RNA-seq 和 CTCF ChIP-seq 数据集的系统整合揭示了 T-ALL 中 TAD 内染色质相互作用和 TAD 边界绝缘的广泛差异。我们的研究确定并关注与 CTCF 介导的绝缘缺失相关的 TAD“融合”​​事件，从而实现 MYC 启动子和远端超级增强子之间的直接相互作用。而且，我们的数据还表明，靶向致癌信号转导或表观遗传调控的小分子抑制剂可以改变白血病中发现的特定 3D 相互作用。总体而言，我们的研究强调了 3D 染色质结构在人类急性白血病中的影响、复杂性和动态特性。