Epigenetic heterogeneity hotspots in human liver disease progression [RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA1099239 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28629100_1.fastq.gz | Fastqsanger.gz | |||
| SRR28629100_2.fastq.gz | Fastqsanger.gz | |||
| SRR28629200_1.fastq.gz | Fastqsanger.gz | |||
| SRR28629200_2.fastq.gz | Fastqsanger.gz | |||
| SRR28629101_1.fastq.gz | Fastqsanger.gz |
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Project description:Disruption of the epigenome is a hallmark of human disease including liver cirrhosis and hepatocellular carcinoma (HCC). While genetic heterogeneity is an established effector of pathologic phenotypes, epigenetic heterogeneity is less well understood. Environmental exposures including hepatitis C viral (HCV) infection and metabolic syndrome alter the liver-specific DNA methylation landscape and influence the onset of liver cancer. Given that currently available treatments are unable to target the most frequently mutated genes in HCC, there is an unmet need for novel therapeutic strategies to prevent or reverse hepatic tumorigenesis, which the epigenome may provide. We performed genome-wide profiling of DNA methylation, copy number, and gene expression landscapes from multiple liver regions from 31 patients with liver disease to examine their crosstalk and define the individual and combinatorial contribution of these processes to liver disease progression. We identify epigenetic heterogeneity hotspots that are conserved across patients. Elevated epigenetic heterogeneity associates with increases in gene expression heterogeneity. Cirrhotic regions comprise two distinct cohorts, one exclusively epigenetic, and a second where epigenetic and copy number variations collaborate. Epigenetic heterogeneity hotspots are enriched for genes central to liver function (e.g., HNF1A) and known tumor suppressors (e.g., RASSF1A). These hotspots encompass genes including ACSL1, ACSL5, MAT1A, and ELFN1, which have phenotypic effects in cell line functional screens, supporting their relevance to hepatocarcinogenesis. Substantial epigenetic heterogeneity arises early in liver disease development, targeting key pathways in the progression and initiation of both cirrhosis and HCC. Integration of epigenetic and transcriptional heterogeneity unveils putative epigenetic regulators of hepatocarcinogenesis.
2024-07-30 | GSE263787 | GEO
Project description:Disruption of the epigenome is a hallmark of human disease including liver cirrhosis and hepatocellular carcinoma (HCC). While genetic heterogeneity is an established effector of pathologic phenotypes, epigenetic heterogeneity is less well understood. Environmental exposures including hepatitis C viral (HCV) infection and metabolic syndrome alter the liver-specific DNA methylation landscape and influence the onset of liver cancer. Given that currently available treatments are unable to target the most frequently mutated genes in HCC, there is an unmet need for novel therapeutic strategies to prevent or reverse hepatic tumorigenesis, which the epigenome may provide. We performed genome-wide profiling of DNA methylation, copy number, and gene expression landscapes from multiple liver regions from 31 patients with liver disease to examine their crosstalk and define the individual and combinatorial contribution of these processes to liver disease progression. We identify epigenetic heterogeneity hotspots that are conserved across patients. Elevated epigenetic heterogeneity associates with increases in gene expression heterogeneity. Cirrhotic regions comprise two distinct cohorts, one exclusively epigenetic, and a second where epigenetic and copy number variations collaborate. Epigenetic heterogeneity hotspots are enriched for genes central to liver function (e.g., HNF1A) and known tumor suppressors (e.g., RASSF1A). These hotspots encompass genes including ACSL1, ACSL5, MAT1A, and ELFN1, which have phenotypic effects in cell line functional screens, supporting their relevance to hepatocarcinogenesis. Substantial epigenetic heterogeneity arises early in liver disease development, targeting key pathways in the progression and initiation of both cirrhosis and HCC. Integration of epigenetic and transcriptional heterogeneity unveils putative epigenetic regulators of hepatocarcinogenesis.
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Project description:Epigenetic heterogeneity hotspots in human liver disease progression [MethylationEPIC Beadchip]
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Project description:Primary outcome(s): The detection rates of epigenetic heterogeneity in primary tumor and plasma from colorectal cancer patients with Methylation-sensitive high resolution melt(MS-HRM).
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Project description:During pancreatic cancer progression, heterogeneous subclonal populations evolve in the primary tumor that possess differing capacities to metastasize and cause patient death. However, the genetics of metastasis reflects that of the primary tumor, and PDAC driver mutations arise early. This raises the possibility than an epigenetic process could be operative late. Using an exceptional resource of paired patient samples, we found that different metastatic subclones from the same patient possessed remarkably divergent malignant properties and global epigenetic programs. Global reprogramming was targeted to thousands of large chromatin domains across the genome that collectively specified malignant divergence. This was maintained by a metabolic shift within the pentose phosphate pathway, independent of KRAS driver mutations. Analysis of paired primary and metastatic tumors from multiple patients uncovered substantial epigenetic heterogeneity in primary tumors, which resolved into a terminally reprogrammed state in metastatic lesions. This supports a model whereby driver mutations accumulate early to initiate pancreatic tumorigenesis, followed by a period of subclonal evolution that generates sufficient intra-tumor heterogeneity for selection of epigenetic programs that may increase fitness during malignant progression and metastatic spread. To map the epigenomic landscape of pancreatic cancer progression as it evolves within patients. RNA-Seq of 2 patients (A13 and A38). Patient A38 included local peritoneal metastasis and 2 distant metastsis (liver and lung mets), and 6AN treated and DMSO control samples. Patient A13 included 2 primary tumors and 1 distant lung metastasis. Each sample has been done with replicates.
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