Three‐dimensional analysis reveals altered chromatin interaction by enhancer inhibitors harbors TCF7L2‐regulated cancer gene signature

Gerrard, Diana L.; Wang, Yao; Gaddis, Malaina; Zhou, Yufan; Wang, Junbai; Witt, Heather; Lin, Shili; Farnham, P; Jin, Victor X.; Frietze, Seth

doi:10.1002/jcb.27449

Cited by 10 publications

(14 citation statements)

References 58 publications

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“…Previous work had developed 3D chromatin structure of pancreatic cancer, but they focused on structural variants detection [ 33 ] by Hi-C and TAD alterations [ 34 , 35 ]. Here, we reported sub-5-kb resolution Hi-C maps to identify contact domain and loop alterations during pancreatic cancer metastasis.…”

Section: Discussionmentioning

confidence: 99%

High-resolution Hi-C maps highlight multiscale 3D epigenome reprogramming during pancreatic cancer metastasis

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

High-resolution Hi-C maps highlight multiscale 3D epigenome reprogramming during pancreatic cancer metastasis

et al. 2021

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“…We, therefore, examined the relationship between higher-order chromatin organization and broad epigenetic domains in PANC1 cells. Genome-wide chromatin contacts were determined by analyzing tethered-chromatin conformation capture (TCC) data in PANC1 [43]. Chromatin contacts were partitioned into topologically associated domains (TADs) and TAD boundary regions using a resolution of 40 kb ( Figure 5A and Figure S6).…”

Section: Hat Inhibitor Treatment Targets Broad Domains That Are Enricmentioning

confidence: 99%

Disruption of Broad Epigenetic Domains in PDAC Cells by HAT Inhibitors

et al. 2019

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The spreading of epigenetic domains has emerged as a distinguishing epigenomic phenotype for diverse cell types. In particular, clusters of H3K27ac- and H3K4me3-marked elements, referred to as super-enhancers, and broad H3K4me3 domains, respectively, have been linked to cell identity and disease states. Here, we characterized the broad domains from different pancreatic ductal adenocarcinoma (PDAC) cell lines that represent distinct histological grades. Our integrative genomic analysis found that human derived cell line models for distinct PDAC grades exhibit characteristic broad epigenetic features associated with gene expression patterns that are predictive of patient prognosis and provide insight into pancreatic cancer cell identity. In particular, we find that genes marked by overlapping Low-Grade broad domains correspond to an epithelial phenotype and hold potential as markers for patient stratification. We further utilize ChIP-seq to compare the effects of histone acetyltransferase (HAT) inhibitors to detect global changes in histone acetylation and methylation levels. We found that HAT inhibitors impact certain broad domains of pancreatic cancer cells. Overall, our results reveal potential roles for broad domains in cells from distinct PDAC grades and demonstrate the plasticity of particular broad epigenomic domains to epigenetic inhibitors.

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“…However the specific role of TCF7L2 in the development of BE is not fully understood. Previous studies have shown that TCG7L2 is closely associated with the development, progression and distant metastasis of various cancers such as pancreatic cancer 41 . The overexpressed TCF7L2 was associated with poor overall survival in patients with glioma 42 .…”

Section: Discussionmentioning

confidence: 98%

Analysis of immune related gene expression profiles and immune cell components in patients with Barrett esophagus

Shi

Guo

Chen

et al. 2022

Sci Rep

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Barrett's esophagus (BE) is a well-known precancerous condition of esophageal adenocarcinoma. However, the immune cells and immune related genes involved in BE development and progression are not fully understood. Therefore, our study attempted to investigate the roles of immune cells and immune related genes in BE patients. The raw gene expression data were downloaded from the GEO database. The limma package in R was used to screen differentially expressed genes (DEGs). Then we performed the least absolute shrinkage and selection operator (LASSO) and random forest (RF) analyses to screen key genes. The proportion of infiltrated immune cells was evaluated using the CIBERSORT algorithm between BE and normal esophagus (NE) samples. The spearman index was used to show the correlations of immune genes and immune cells. Receiver operating characteristic (ROC) curves were used to assess the diagnostic value of key genes in BE. A total of 103 differentially expressed immune-related genes were identified between BE samples and normal samples. Then, 7 genes (CD1A, LTF, FABP4, PGC, TCF7L2, INSR,SEMA3C) were obtained after Lasso analysis and RF modeling. CIBERSORT analysis revealed that resting CD4 T memory cells and gamma delta T cells were present at significantly lower levels in BE samples. Moreover, plasma cell and regulatory T cells were present at significantly higher levels in BE samples than in NE samples. INSR had the highest AUC values in ROC analysis. We identified 7 immune related genes and 4 different immune cells in our study, that may play vital roles in the occurrence and development of BE. Our findings improve the understanding of the molecular mechanisms of BE.

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Three‐dimensional analysis reveals altered chromatin interaction by enhancer inhibitors harbors TCF7L2‐regulated cancer gene signature

Cited by 10 publications

References 58 publications

High-resolution Hi-C maps highlight multiscale 3D epigenome reprogramming during pancreatic cancer metastasis

High-resolution Hi-C maps highlight multiscale 3D epigenome reprogramming during pancreatic cancer metastasis

Disruption of Broad Epigenetic Domains in PDAC Cells by HAT Inhibitors

Analysis of immune related gene expression profiles and immune cell components in patients with Barrett esophagus

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