Comprehensive analyses of partially methylated domains and differentially methylated regions in esophageal cancer reveal both cell-type- and cancer-specific epigenetic regulation
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE210220 | GEO | 2023/08/04
REPOSITORIES: GEO
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Project description:BackgroundAs one of the most common malignancies, esophageal cancer has two subtypes, squamous cell carcinoma and adenocarcinoma, arising from distinct cells-of-origin. Distinguishing cell-type-specific molecular features from cancer-specific characteristics is challenging.ResultsWe analyze whole-genome bisulfite sequencing data on 45 esophageal tumor and nonmalignant samples from both subtypes. We develop a novel sequence-aware method to identify large partially methylated domains (PMDs), revealing profound heterogeneity at both methylation level and genomic distribution of PMDs across tumor samples. We identify subtype-specific PMDs that are associated with repressive transcription, chromatin B compartments and high somatic mutation rate. While genomic locations of these PMDs are pre-established in normal cells, the degree of loss is significantly higher in tumors. We find that cell-type-specific deposition of H3K36me2 may underlie genomic distribution of PMDs. At a smaller genomic scale, both cell-type- and cancer-specific differentially methylated regions (DMRs) are identified for each subtype. Using binding motif analysis within these DMRs, we show that a cell-type-specific transcription factor HNF4A maintains the binding sites that it generates in normal cells, while establishing new binding sites cooperatively with novel partners such as FOSL1 in esophageal adenocarcinoma. Finally, leveraging pan-tissue single-cell and pan-cancer epigenomic datasets, we demonstrate that a substantial fraction of cell-type-specific PMDs and DMRs identified here in esophageal cancer are actually markers that co-occur in other cancers originating from related cell types.ConclusionsThese findings advance our understanding of DNA methylation dynamics at various genomic scales in normal and malignant states, providing novel mechanistic insights into cell-type- and cancer-specific epigenetic regulations.
| S-EPMC10463844 | biostudies-literature
Project description:As one of the most common malignancies, esophageal cancer has two subtypes, squamous cell carcinoma (ESCC) and adenocarcinoma (EAC), arising from distinct cells-of-origin. However, distinguishing cell-type-specific molecular features from cancer-specific characteristics has been challenging. Here, we analyze whole-genome bisulfite sequencing (WGBS) data on 45 esophageal tumor and nonmalignant samples from both subtypes. We develop a novel sequence-aware method to identify large partially methylated domains (PMDs), revealing profound heterogeneity at both the methylation level (depth) and genomic distribution (breadth) of PMDs across tumor samples. We identify subtype-specific PMDs, which are associated with repressive transcription, chromatin B compartments and high somatic mutation rate. While the genomic locations of these PMDs are pre-established in normal cells, the degree of loss is significantly higher in tumors. We find that cell-type-specific deposition of H3K36me2 may underlie the genomic distribution PMDs. At a smaller genomic scale, both cell-type- and cancer-specific differentially methylated regions (DMRs) are identified for each subtype. Using binding motif analysis within these DMRs, we show that a cell-type-specific transcription factor such as HNF4A can maintain the binding sites that it establishes in normal cells, while being recruited to new binding sites with novel partners such as FOSL1 in cancer. Finally, leveraging pan-tissue single-cell and pan-cancer epigenomic datasets, we demonstrate that a substantial fraction of the cell-type-specific PMDs and DMRs identified here in esophageal cancer, are actually markers that co-occur in other cancers originating from related cell types. These findings advance our understanding of the DNA methylation dynamics at various genomic scales in normal and malignant states, providing novel mechanistic insights into cell-type- and cancer-specific epigenetic regulations. Whole-genome bisulfite sequencing (WGBS) for EAC ESO26 cell line and ESCC TE5 cell line.
2023-08-04 | GSE210218 | GEO
Project description:As one of the most common malignancies, esophageal cancer has two subtypes, squamous cell carcinoma (ESCC) and adenocarcinoma (EAC), arising from distinct cells-of-origin. However, distinguishing cell-type-specific molecular features from cancer-specific characteristics has been challenging. Here, we analyze whole-genome bisulfite sequencing (WGBS) data on 45 esophageal tumor and nonmalignant samples from both subtypes. We develop a novel sequence-aware method to identify large partially methylated domains (PMDs), revealing profound heterogeneity at both the methylation level (depth) and genomic distribution (breadth) of PMDs across tumor samples. We identify subtype-specific PMDs, which are associated with repressive transcription, chromatin B compartments and high somatic mutation rate. While the genomic locations of these PMDs are pre-established in normal cells, the degree of loss is significantly higher in tumors. We find that cell-type-specific deposition of H3K36me2 may underlie the genomic distribution PMDs. At a smaller genomic scale, both cell-type- and cancer-specific differentially methylated regions (DMRs) are identified for each subtype. Using binding motif analysis within these DMRs, we show that a cell-type-specific transcription factor such as HNF4A can maintain the binding sites that it establishes in normal cells, while being recruited to new binding sites with novel partners such as FOSL1 in cancer. Finally, leveraging pan-tissue single-cell and pan-cancer epigenomic datasets, we demonstrate that a substantial fraction of the cell-type-specific PMDs and DMRs identified here in esophageal cancer, are actually markers that co-occur in other cancers originating from related cell types. These findings advance our understanding of the DNA methylation dynamics at various genomic scales in normal and malignant states, providing novel mechanistic insights into cell-type- and cancer-specific epigenetic regulations. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for histone H3K36me2 in EAC OE19 cell line, ESCC KYSE70 and TE5 cell lines.
2023-08-04 | GSE210219 | GEO
Project description:Comprehensive analyses of partially methylated domains and differentially methylated regions in esophageal cancer reveal both cell-type- and cancer-specific epigenetic regulation
| PRJNA864780 | ENA
Project description:Comprehensive analyses of partially methylated domains and differentially methylated regions in esophageal cancer reveal both cell-type- and cancer-specific epigenetic regulation [WGBS]
| PRJNA864787 | ENA
Project description:Comprehensive analyses of partially methylated domains and differentially methylated regions in esophageal cancer reveal both cell-type- and cancer-specific epigenetic regulation [ChIP-Seq]
| PRJNA864786 | ENA
Project description:BACKGROUND: Aberrant methylation at imprinted differentially methylated regions (DMRs) in human 11p15.5 has been reported in many tumors including hepatoblastoma. However, the methylation status of imprinted DMRs in imprinted loci scattered through the human genome has not been analyzed yet in any tumors. METHODS: The methylation statuses of 33 imprinted DMRs were analyzed in 12 hepatoblastomas and adjacent normal liver tissue by MALDI-TOF MS and pyrosequencing. Uniparental disomy (UPD) and copy number abnormalities were investigated with DNA polymorphisms. RESULTS: Among 33 DMRs analyzed, 18 showed aberrant methylation in at least 1 tumor. There was large deviation in the incidence of aberrant methylation among the DMRs. KvDMR1 and IGF2-DMR0 were the most frequently hypomethylated DMRs. INPP5Fv2-DMR and RB1-DMR were hypermethylated with high frequencies. Hypomethylation was observed at certain DMRs not only in tumors but also in a small number of adjacent histologically normal liver tissue, whereas hypermethylation was observed only in tumor samples. The methylation levels of long interspersed nuclear element-1 (LINE-1) did not show large differences between tumor tissue and normal liver controls. Chromosomal abnormalities were also found in some tumors. 11p15.5 and 20q13.3 loci showed the frequent occurrence of both genetic and epigenetic alterations. CONCLUSIONS: Our analyses revealed tumor-specific aberrant hypermethylation at some imprinted DMRs in 12 hepatoblastomas with additional suggestion for the possibility of hypomethylation prior to tumor development. Some loci showed both genetic and epigenetic alterations with high frequencies. These findings will aid in understanding the development of hepatoblastoma.
| S-EPMC3880457 | biostudies-literature
Project description:BackgroundImprinted genes are regulated by DNA methylation at imprinting-associated differentially methylated regions (iDMRs). Abnormal expression of imprinted genes is implicated in imprinting disorders and tumors. In colorectal cancer (CRC), methylation and imprinting status of the IGF2/H19 domain have been studied. However, no comprehensive methylation analysis of iDMRs in CRC has been reported. Furthermore, the relationship between iDMR methylation status and other methylation-related issues, such as CpG island methylator phenotype (CIMP) and long interspersed element-1 (LINE-1) methylation, remains unclear.ResultsWe analyzed the methylation status of 38 iDMRs in 106 CRC patients. We also investigated CIMP, LINE-1 methylation, KRAS and BRAF gene mutations, and loss of imprinting (LOI) of IGF2. We further examined the relationship between these factors and clinicopathological factors. The overall trend in iDMR methylation was towards hypermethylation, and iDMRs could be grouped into three categories: susceptible, resistant, and intermediate-to-aberrant methylation. The susceptible and resistant iDMRs consisted of all types of iDMR (gametic and somatic, maternally and paternally methylated). Hypermethylation of multiple iDMRs (HyMiD)-positive status was statistically associated with CIMP-positive status, but not associated with mutations in the BRAF and KRAS genes. HyMiD-positive status was inversely associated with LINE-1 methylation. Among four iDMRs within the IGF2/H19 domain, IGF2-DMR0 hypomethylation occurred most frequently, but was not associated with IGF2 LOI. Finally, we statistically calculated predictive prognostic scores based on aberrant methylation status of three iDMRs.ConclusionIn CRC tissues, some iDMRs were susceptible to hypermethylation independent of the type of iDMR and genomic sequence. Although HyMiD-positive status was associated with CIMP-positive status, this was independent of the BRAF and KRAS pathways, which are responsible for CIMP. Since IGF2-DMR0 hypomethylation and aberrant methylation of other iDMRs within the IGF2/H19 domain were not associated with IGF2 LOI, dysfunction of any of the molecular components related to imprinting regulation may be involved in IGF2 LOI. The prognostic score calculated based on aberrant methylation of three iDMRs has potential clinical applications as a prognostic predictor in patients. Further study is required to understand the biological significance of, and mechanisms behind, aberrant methylation of iDMRs and IGF2 LOI in CRCs.
| S-EPMC6278095 | biostudies-literature
Project description:Obesity with adiposity is a common disorder in modern days, influenced by environmental factors such as eating and lifestyle habits and affecting the epigenetics of adipose-based gene regulations and metabolic pathways in colorectal cancer (CRC). We compared epigenetic changes of differentially methylated regions (DMR) of genes in colon tissues of 225 colon cancer cases (154 non-obese and 71 obese) and 15 healthy non-obese controls by accessing The Cancer Genome Atlas (TCGA) data. We applied machine-learning-based analytics including generalized regression (GR) as a confirmatory validation model to identify the factors that could contribute to DMRs impacting colon cancer to enhance prediction accuracy. We found that age was a significant predictor in obese cancer patients, both alone (p = 0.003) and interacting with hypomethylated DMRs of ZBTB46, a tumor suppressor gene (p = 0.008). DMRs of three additional genes: HIST1H3I (p = 0.001), an oncogene with a hypomethylated DMR in the promoter region; SRGAP2C (p = 0.006), a tumor suppressor gene with a hypermethylated DMR in the promoter region; and NFATC4 (p = 0.006), an adipocyte differentiating oncogene with a hypermethylated DMR in an intron region, are also significant predictors of cancer in obese patients, independent of age. The genes affected by these DMR could be potential novel biomarkers of colon cancer in obese patients for cancer prevention and progression.
| S-EPMC9142939 | biostudies-literature
Project description:Differentially DNA methylated regions (DMRs) inform on the role of epigenetic changes in cancer. We present Rocker-meth, a new computational method exploiting a heterogeneous hidden Markov model to detect DMRs across multiple experimental platforms. Through an extensive comparative study, we first demonstrate Rocker-meth excellent performance on synthetic data. Its application to more than 6,000 methylation profiles across 14 tumor types provides a comprehensive catalog of tumor type-specific and shared DMRs, and agnostically identifies cancer-related partially methylated domains (PMD). In depth integrative analysis including orthogonal omics shows the enhanced ability of Rocker-meth in recapitulating known associations, further uncovering the pan-cancer relationship between DNA hypermethylation and transcription factor deregulation depending on the baseline chromatin state. Finally, we demonstrate the utility of the catalog for the study of colorectal cancer single-cell DNA-methylation data.
| S-EPMC8563962 | biostudies-literature