Pancreatic cancer’s poor prognosis is caused by distal metastasis, which is associated with epigenetic changes. However, the role of the 3D epigenome in pancreatic cancer biology, especially its metastasis, remains unclear. Here, we developed high-resolution 3D epigenomic maps of cells derived from normal pancreatic epithelium, primary and metastatic pancreatic cancer by in situ Hi-C, ChIP-seq, ATAC-seq, and RNA-seq to identify key genes involved in pancreatic cancer metastasis We found that A/B compartments, contact domains, and chromatin loops changed significantly in metastatic pancreatic cancer cells, which are associated with epigenetic state alterations. Moreover, we found that upregulated genes, which were located in switched compartments, changed contact domains, and metastasis-specific enhancer-promoter loops, were related to cancer metastasis and poor prognosis of patients with pancreatic cancer. We also found that transcription factors in specific enhancer-promoter loop formation were also associated with metastasis. Finally we demonstrated that LIPC, looped to metastasis-specific enhancers, could promote pancreatic cancer metastasis. These results highlight the multiscale 3D epigenome reprogramming during pancreatic cancer metastasis and expand our knowledge of mechanisms of gene regulation during pancreatic cancer metastasis.

中文翻译：

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高分辨率 Hi-C 图突出了胰腺癌转移过程中的多尺度 3D 表观基因组重编程

胰腺癌的不良预后是由远端转移引起的，这与表观遗传变化有关。然而，3D 表观基因组在胰腺癌生物学中的作用，尤其是其转移，仍不清楚。在这里，我们通过原位 Hi-C、ChIP-seq、ATAC-seq 和 RNA-seq 开发了源自​​正常胰腺上皮、原发性和转移性胰腺癌的细胞的高分辨率 3D 表观基因组图谱，以识别参与胰腺癌的关键基因转移 我们发现转移性胰腺癌细胞中的 A/B 区室、接触域和染色质环发生了显着变化，这与表观遗传状态改变有关。此外，我们发现上调基因，这些基因位于转换的隔室、改变的接触域和转移特异性增强子-启动子环，与胰腺癌患者的癌症转移和预后不良有关。我们还发现特定增强子-启动子环形成中的转录因子也与转移有关。最后，我们证明了与转移特异性增强子相连的 LIPC 可以促进胰腺癌转移。这些结果突出了胰腺癌转移过程中的多尺度 3D 表观基因组重编程，并扩大了我们对胰腺癌转移过程中基因调控机制的认识。