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BACKGROUND

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.

METHODS

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 RESULTS: 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.

CONCLUSIONS

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.

BACKGROUND

METHODS

CONCLUSIONS

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.

背景

胰腺癌预后不良是由远处转移引起的，而远处转移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，尤其是在转移中的作用，仍不清楚。

方法

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，以鉴定参与胰腺癌转移的关键基因。

结果

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著变化，这与表观遗传状态的改变有关。此外，我们发现上调的基因位于开关区室中，改变了接触域和转移特异性增强子-启动子环，与癌症转移和胰腺癌患者的不良预后有关。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环化的 LIPC 可以促进胰腺癌转移。