Previous studies demonstrated that aberrant chromatin interactions contribute to tumorigenesis, but no detailed studies have delineated a 3D epigenomic map of cancer metastasis, especially for pancreatic cancer. These chromatin loops are usually mediated by CCCTC-binding factor (CTCF), and often connect regulatory regions, such as enhancer-promoter loops. With increased sequencing depth, high resolution Hi-C data showed that there are contact domains located in megabase-sized chromatin domains and allowed the detection of loops across the entire genome. Subsequent analyses showed that compartments are partitioned into ~ 1 Mb in size, called “topologically associating domains”. Hi-C, a genome-wide chromosome conformation capture assay, showed that the human genome is folded three-dimensionally in the nucleus and divided into several active or inactive compartments, named A or B. However, as an integral part of epigenetic information, the 3D organization of chromatin and its reprogramming during tumor metastasis remain to be elucidated, and even less is known about pancreatic cancer.Īppropriate gene expression is determined by correct chromatin folding. Increasing knowledge of epigenetics has shown that DNA methylation and histone modification are associated with pancreatic cancer pathobiology and subtyping, and they change significantly during pancreatic cancer progression.
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A recent whole-genome sequencing study showed that there are few heterogeneities of known driver mutations in primary and metastatic pancreatic cancer tissues, indicating that genetic mutations per se may have relatively less influence on metastasis. It is well known that genetic mutations play pivotal roles in primary tumorigenesis however, no “metastasis-specific” genetic mutations have been identified. Therefore, the identification of fundamental mechanisms involved in pancreatic cancer metastasis would provide valuable information for its diagnosis and treatment. Currently, the 5-year survival rate of patients with distant metastasis is only 3%, which is much smaller than that of patients with localized lesions. Despite the significant progress in the treatment of most human cancers, pancreatic cancer continues to be a deadly malignancy due to its distant metastasis and difficulty in early diagnosis. The incidence of pancreatic cancer has steadily risen in recent years. 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. Finally we demonstrated that LIPC, looped to metastasis-specific enhancers, could promote pancreatic cancer metastasis.
We also found that transcription factors in specific enhancer-promoter loop formation were also associated with metastasis.
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 found that A/B compartments, contact domains, and chromatin loops changed significantly in metastatic pancreatic cancer cells, which are associated with epigenetic state alterations. 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 However, the role of the 3D epigenome in pancreatic cancer biology, especially its metastasis, remains unclear. Pancreatic cancer’s poor prognosis is caused by distal metastasis, which is associated with epigenetic changes.
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