Genome-wide DNA methylation markers associated with metabolic liver cancer
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PROVIDER: PRJNA1185240 | ENA |
REPOSITORIES: ENA
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Project description:Background and Aims: Metabolic liver disease is the fastest rising cause of hepatocellular carcinoma (HCC) worldwide, but the underlying molecular processes that drive HCC development in the setting of metabolic perturbations are unclear. We investigated the role of aberrant DNA methylation in metabolic HCC development in a multicenter international study. Results: We enrolled 272 metabolic HCC patients and 316 control patients with metabolic liver disease from six sites. Fifty-five differentially methylated CpGs were identified; 33 hypermethylated and 22 hypomethylated in cases versus controls. The panel of 55 CpGs discriminated between cases and controls with AUC=0.79 (95%CI=0.71-0.87), sensitivity=0.77 (95%CI=0.66-0.89), and specificity=0.74 (95%CI=0.64-0.85). The 55-CpG classifier panel performed better than a base model that comprised age, sex, race, and diabetes mellitus (AUC=0.65, 95%CI=0.55-0.75, sensitivity=0.62 (95%CI=0.49-0.75) and specificity=0.64 (95%CI=0.52-0.75). A multifactorial model that combined the 55 CpGs with age, sex, race, and diabetes, yielded AUC=0.78 (95%CI=0.70-0.86), sensitivity=0.81 (95%CI=0.71-0.92), and specificity=0.67 (95%CI=0.55-0.78). Conclusions: A panel of 55 blood leukocyte DNA methylation markers differentiates patients with metabolic HCC from control patients with benign metabolic liver disease, with a slightly higher sensitivity when combined with demographic and clinical information.
2025-02-26 | GSE281691 | GEO
Project description:Background and aimsMetabolic liver disease is the fastest rising cause of hepatocellular carcinoma (HCC) worldwide, but the underlying molecular processes that drive HCC development in the setting of metabolic perturbations are unclear. We investigated the role of aberrant DNA methylation in metabolic HCC development in a multicenter international study.MethodsWe used a case-control design, frequency-matched on age, sex, and study site. Genome-wide profiling of peripheral blood leukocyte DNA was performed using the 850k EPIC array. Cell type proportions were estimated from the methylation data. The study samples were split 80% and 20% for training and validation. Differential methylation analysis was performed with adjustment for cell type, and we generated area under the receiver-operating curves (ROC-AUC).ResultsWe enrolled 272 metabolic HCC patients and 316 control patients with metabolic liver disease from six sites. Fifty-five differentially methylated CpGs were identified; 33 hypermethylated and 22 hypomethylated in cases versus controls. The panel of 55 CpGs discriminated between cases and controls with AUC=0.79 (95%CI=0.71-0.87), sensitivity=0.77 (95%CI=0.66-0.89), and specificity=0.74 (95%CI=0.64-0.85). The 55-CpG classifier panel performed better than a base model that comprised age, sex, race, and diabetes mellitus (AUC=0.65, 95%CI=0.55-0.75, sensitivity=0.62 (95%CI=0.49-0.75) and specificity=0.64 (95%CI=0.52-0.75). A multifactorial model that combined the 55 CpGs with age, sex, race, and diabetes, yielded AUC=0.78 (95%CI=0.70-0.86), sensitivity=0.81 (95%CI=0.71-0.92), and specificity=0.67 (95%CI=0.55-0.78).ConclusionsA panel of 55 blood leukocyte DNA methylation markers differentiates patients with metabolic HCC from control patients with benign metabolic liver disease, with a slightly higher sensitivity when combined with demographic and clinical information.
| S-EPMC11601684 | biostudies-literature
Project description:Liver TET1 promotes metabolic dysfunction-associated steatotic liver disease
| PRJNA1209064 | ENA
Project description:Background: Fontan-associated liver disease (FALD) is a common sequelae of single-ventricle patients palliated with the Fontan operation. FALD severity can impact clinical decisions; however, the pathophysiology of FALD progression is unknown. Methods: Single-cell spatial transcriptomics (ST) was performed on liver explant tissue sections from FALD patients with early and advanced fibrosis using CosMxTM Spatial Molecular Imaging with in-situ hybridization of 6000 genes (n=2). Immunofluorescence for hepatic zonation and cellular stress markers was used to confirm protein expression based on ST analysis in biopsy and explant FALD tissues (n=17). Results: Unbiased clustering yielded 12 liver cell types, comprising five subtypes of hepatocytes. FALD with advanced fibrosis demonstrated the expansion of mid-zonal hepatocytes, accompanied by the loss of metabolic markers associated with canonical pericentral and periportal hepatocytes. Advanced FALD hepatocytes uniquely demonstrated increased cellular stress and a redundant metabolic phenotype. Advanced FALD hepatocytes changed into a senescent-like state, which we have termed hepatocyte metabolic exhaustion. Protein expression analysis confirmed metabolic exhaustion within hepatocytes and upregulation of cellular stress markers in advanced FALD tissue specimens. Immunofluorescence staining of FALD samples demonstrated a disruption of zonation and a significant increase in heat shock protein 70 (HSP70). HSP70 expression strongly correlated with the congestive hepatic fibrosis (CHF) score. Conclusions: Single-cell ST has identified a population of hepatocytes with features of metabolic exhaustion and cellular stress unique to advanced FALD.
2026-02-04 | GSE310443 | GEO
Project description:Heritable epigenetic factors can contribute to complex disease etiology. In this study we examine, on a global scale, the contribution of DNA methylation to complex traits that are precursors to heart disease, diabetes and osteoporosis. We profiled DNA methylation patterns in the liver using bisulfite sequencing in 90 mouse inbred strains, genome-wide expression levels, proteomics, metabolomics and sixty-eight clinical traits, and performed epigenome-wide association studies (EWAS). We found associations with numerous clinical traits including bone mineral density, plasma cholesterol, insulin resistance, gene expression, protein and metabolite levels. A large proportion of associations were unique to EWAS and were not identified using GWAS. Methylation levels were regulated by genetics largely in cis, but we also found evidence of trans regulation, and we demonstrate that genetic variation in the methionine synthase reductase gene Mtrr affects methylation of hundreds of CpGs throughout the genome. Our results indicate that natural variation in methylation levels contributes to the etiology of complex clinical traits. Reduced representation bisulfite sequencing in mouse strains using liver genomic DNA
2015-04-02 | E-GEOD-67507 | biostudies-arrayexpress
Project description:Background: DNA methylation is an important component of epigenetic modifications that influences the transcriptional machinery and is aberrant in many human diseases. In particular, dysregulation of promoter methylation in cancer has already been shown to be associated with repression of tumor suppressors and activation of oncogenes. In addition, detection of altered promoter methylation status is suitable for the design of diagnostic or prognostic tests. In this study we present a new methodological approach for the robust identification of promoter methylation markers and the first genome-wide study for the detection of methylation markers in melanoma. Methods and Findings: Genome-wide promoter methylation and gene expression of ten early passage melanoma cell strains are compared to newborn and adult normal melanocytes. For the identification of markers we applied linear mixed effect models (LME) in combination with a series of filters based on the localization of promoter methylation relative to the transcription start site, overall promoter CpG content, and differential gene expression. The aim of this methodology is to identify markers whose promoter differential methylation is likely to be functionally related to differential expression. We identified 76 markers, 68 hyper- and 8-hypo-methylated in melanomas (LME P<0.05). Promoter methylation profiles and differential expression of five of these markers were successfully validated. In addition, promoter demethylation following Aza treatment consistently restored expression of markers hyper-methylated in melanoma. Conclusions: The proposed methodology allows the identification of robust markers and can be applied to other experimental scenarios where promoter methylation is evaluated. More importantly, the list of markers represents the first systematic effort in the identification of methylation markers in melanoma. Many of the identified markers were not previously known to be regulated by promoter methylation and/or associated with this or other types of cancer.
2009-05-26 | GSE13706 | GEO
Project description:Liver fibrosis was found to be existed in all kinds of chronic liver diseases. Many studies suggested that DNA methylation was related with the pathogenesis of liver fibrosis. The aim of this study was to quantitatively detect DNA methylation changes in the whole genome in fibrotic liver tissues. Carbon tetrachloride (CCl4) was used to induce male mice liver fibrosis by intraperitoneal injection for 4 weeks. A genome-wide methylome analysis was performed using 850K BeadChips assays. The methylation status of 27 CpG dinucleotides located in 3 genes was detected by pyrosequencing to confirm chips data accuracy, and their mRNA expressions were examined by RT-qPCR methods. A total of 130,068 differentially methylated sites (DMS, 58,474 hypermethylated and 71,594 hypomethylated) between fibrotic liver tissues and control mice liver tissues were identified by the 850k BeadChips array. They distribute in each chromosome. Recognition of apoptotic cell, Notch and p38MAPK et al activities were significantly enriched in the Gene Ontology (GO) analyses. Cholesterol metabolism, bile secretion and more biosynthesis and metabolism pathway were enriched in KEGG pathway analyses. Many classical pathways of fibrogenesis and liver activity, as well as more biosynthetic and metabolic pathways, were found to be related to methylation changes. Our result facilitates future research for clinical application.
2023-01-11 | GSE193182 | GEO
Project description:Hepatocytes that have differentiated from human embryonic stem cells have great potential for the treatment of liver disease as well as for drug testing. Moreover, in vitro hepatogenesis is a powerful model system for studying the molecular mechanisms underlying liver development. DNA methylation is an important epigenetic mechanism that influences differential gene expression during embryonic development. We profiled gene expression and DNA methylation of three cell states of in vitro hepatogenesis—human embryonic stem cells, endoderm progenitors, and mature hepatocytes—using microarray analysis. Among 525 state-specific expressed genes, 67 showed significant negative correlation between gene expression and DNA methylation. State-specific expression and methylation of target genes were validated by quantitative reverse transcription–PCR and pyrosequencing, respectively. To elucidate genome-scale methylation changes beyond the promoter, we also performed high-throughput sequencing of methylated DNA captured by MBD2 protein [see SRA link below]. We found dynamic methylation changes in intergenic regions of the human genome during differentiation. Conclusion: This study provides valuable methylation markers for the lineage commitment of in vitro hepatogenesis and should help elucidate the molecular mechanisms underlying stem cell differentiation and liver development.
2011-06-10 | GSE25047 | GEO
Project description:Genome-wide DNA methylation profiling was performed on non-cancerous and cancerous liver tissue samples obtained from patients with MASH using the Illumina Infinium HumanMethylation450 BeadChip.
2025-08-30 | GSE304513 | GEO
Project description:Heritable epigenetic factors can contribute to complex disease etiology. In this study we examine, on a global scale, the contribution of DNA methylation to complex traits that are precursors to heart disease, diabetes and osteoporosis. We profiled DNA methylation patterns in the liver using bisulfite sequencing in 90 mouse inbred strains, genome-wide expression levels, proteomics, metabolomics and sixty-eight clinical traits, and performed epigenome-wide association studies (EWAS). We found associations with numerous clinical traits including bone mineral density, plasma cholesterol, insulin resistance, gene expression, protein and metabolite levels. A large proportion of associations were unique to EWAS and were not identified using GWAS. Methylation levels were regulated by genetics largely in cis, but we also found evidence of trans regulation, and we demonstrate that genetic variation in the methionine synthase reductase gene Mtrr affects methylation of hundreds of CpGs throughout the genome. Our results indicate that natural variation in methylation levels contributes to the etiology of complex clinical traits.
2015-04-02 | GSE67507 | GEO