Abstract
BackgroundPancreatic 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.MethodsHere, 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 metastasisResultsWe 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.ConclusionsThese results highlight the multiscale 3D epigenome reprogramming during pancreatic cancer metastasis and expand our knowledge of mechanisms of gene regulation during pancreatic cancer metastasis.
Highlights
Pancreatic cancer’s poor prognosis is caused by distal metastasis, which is associated with epigenetic changes
Global reprogramming of the 3D epigenome during pancreatic cancer metastasis To investigate the 3D organization of chromatin of pancreatic cancer, we created high-resolution High throughput variant of chromosome conformation capture (Hi-C) maps of normal pancreatic cells (HPNE) and pancreatic cancer cells derived from the head of pancreas (PANC-1) and liver metastasis (Capan-1) by in situ Hi-C
These results demonstrated concordance between different types of sequencing and provided preliminary evidence that 3D epigenome reprogramming did exist in pancreatic cancer metastasis; the similarity between normal and primary and apparent differences of the 3D epigenome in metastasis were consistent with other epigenetic studies of pancreatic cancer metastasis [20, 22]
Summary
Pancreatic cancer’s poor prognosis is caused by distal metastasis, which is associated with epigenetic changes. The role of the 3D epigenome in pancreatic cancer biology, especially its metastasis, remains unclear. As an integral part of epigenetic information [5], the 3D organization of chromatin and its reprogramming during tumor metastasis remain to be elucidated, and even less is known about pancreatic cancer. High resolution Hi-C data showed that there are contact domains located in megabasesized chromatin domains [8] and allowed the detection of loops across the entire genome. These chromatin loops are usually mediated by CCCTC-binding factor (CTCF) [8], and often connect regulatory regions, such as enhancer-promoter loops. Previous studies demonstrated that aberrant chromatin interactions contribute to tumorigenesis [9, 10], but no detailed studies have delineated a 3D epigenomic map of cancer metastasis, especially for pancreatic cancer
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