Dataset Information

Comprehensive analysis of H3K27me3 LOCKs under different DNA methylation contexts reveal epigenetic redistribution in tumorigenesis

ABSTRACT: Histone modification H3K27me3 is crucial for normal development and is implicated in many diseases, including cancer. H3K27me3 peaks form clusters called Large Organized Chromatin Lysine Domains (LOCKs) that span several hundred kilobases. In this study, we identified H3K27me3 LOCKs in 109 normal samples from the Roadmap project and categorized them into long and short LOCKs. Long LOCKs are preferentially linked to developmental functions, while short LOCKs strongly repress gene expression and are enriched in poised promoters. By examining LOCK distribution in common PMDs (Partially Methylated Domains) and HMDs (Highly Methylated Domains), we discovered that long LOCKs are primarily located in short-PMDs (S-PMDs). Oncogenes within S-PMDs are often covered by long LOCKs, exerting the strongest repression. Analyzing LOCKs in esophageal squamous cell carcinoma (ESCC) and breast cancer (BRCA) cell lines and their normal counterparts, we observed a transition of long LOCK distribution from S-PMDs, to intermediate-PMDs (I-PMDs) and long-PMDs (L-PMDs). Interestingly, a substantial subset of tumor-gain long LOCKs within I-PMDs (23%-40%) and L-PMDs (28%-61%) in BRCA exhibit reduced H3K9me3 modification, indicating H3K27me3 compensates for H3K9me3 loss in tumor. Besides, genes upregulated upon short LOCK loss in tumors are frequently poised promoter genes in normal cells and are transcriptionally regulated by ETS1. These results highlight the role of H3K27me3 LOCKs in various epigenomic contexts and their involvement in cancer biology, revealing underlying epigenetic mechanisms.

ORGANISM(S): Homo sapiens

PROVIDER: GSE270715 | GEO | 2025/01/18

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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.

Dataset Information

Comprehensive analysis of H3K27me3 LOCKs under different DNA methylation contexts reveal epigenetic redistribution in tumorigenesis

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets