Epigenomic signatures in liver and blood of Wilson disease patients include hypermethylation of liver-specific enhancers
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA482624 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7587010.fastq.gz | Fastqsanger.gz | |||
| SRR7587020.fastq.gz | Fastqsanger.gz | |||
| SRR7587030.fastq.gz | Fastqsanger.gz | |||
| SRR7587040.fastq.gz | Fastqsanger.gz | |||
| SRR7587050.fastq.gz | Fastqsanger.gz |
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Project description:Wilson disease (WD) is an autosomal recessive disease caused by mutations in ATP7B encoding a copper transporter. Consequent copper accumulation results in a variable WD clinical phenotype involving hepatic, neurologic, and psychiatric symptoms, without clear genotype-phenotype correlations. The goal of this study was to analyze alterations in DNA methylation at the whole-genome level in liver and blood from patients with WD to investigate epigenomic alterations associated with WD diagnosis and phenotype. We used whole-genome bisulfite sequencing (WGBS) to examine distinct cohorts of WD subjects to determine whether DNA methylation could differentiate patients from healthy subjects and subjects with other liver diseases and distinguish between different WD phenotypes. WGBS analyses in liver identified 969 hypermethylated and 871 hypomethylated differentially methylated regions (DMRs) specifically identifying patients with WD, including 18 regions with genome-wide significance. WD-specific liver DMRs were associated with genes enriched for functions in folate and lipid metabolism and acute inflammatory response and could differentiate early from advanced fibrosis in WD patients. Functional annotation revealed that WD-hypermethylated liver DMRs were enriched in liver-specific enhancers, flanking active liver promoters, and binding sites of liver developmental transcription factors, including Hepatocyte Nuclear Factor 4 alpha (HNF4A), Retinoid X Receptor alpha (RXRA), Forkhead Box A1 (FOXA1), and FOXA2. DMRs associated with WD progression were also identified, including 15 with genome-wide significance. However, WD DMRs in liver were not related to large-scale changes in proportions of liver cell types. DMRs detected in blood differentiated WD patients from healthy and disease control subjects, and distinguished between patients with hepatic and neurologic WD manifestations. WD phenotype DMRs corresponded to genes enriched for functions in mental deterioration, abnormal B cell physiology, and as members of the polycomb repressive complex 1 (PRC1). 44 DMRs associated with WD phenotype tested in a small validation cohort had a predictive value of 0.9. We identified a disease-mechanism relevant epigenomic signature of WD that reveals new insights into potential biomarkers and treatments for this complex monogenic disease.
2019-02-14 | GSE117593 | GEO
Project description:BackgroundWilson disease (WD) is an autosomal recessive disease caused by mutations in ATP7B encoding a copper transporter. Consequent copper accumulation results in a variable WD clinical phenotype involving hepatic, neurologic, and psychiatric symptoms, without clear genotype-phenotype correlations. The goal of this study was to analyze alterations in DNA methylation at the whole-genome level in liver and blood from patients with WD to investigate epigenomic alterations associated with WD diagnosis and phenotype. We used whole-genome bisulfite sequencing (WGBS) to examine distinct cohorts of WD subjects to determine whether DNA methylation could differentiate patients from healthy subjects and subjects with other liver diseases and distinguish between different WD phenotypes.ResultsWGBS analyses in liver identified 969 hypermethylated and 871 hypomethylated differentially methylated regions (DMRs) specifically identifying patients with WD, including 18 regions with genome-wide significance. WD-specific liver DMRs were associated with genes enriched for functions in folate and lipid metabolism and acute inflammatory response and could differentiate early from advanced fibrosis in WD patients. Functional annotation revealed that WD-hypermethylated liver DMRs were enriched in liver-specific enhancers, flanking active liver promoters, and binding sites of liver developmental transcription factors, including Hepatocyte Nuclear Factor 4 alpha (HNF4A), Retinoid X Receptor alpha (RXRA), Forkhead Box A1 (FOXA1), and FOXA2. DMRs associated with WD progression were also identified, including 15 with genome-wide significance. However, WD DMRs in liver were not related to large-scale changes in proportions of liver cell types. DMRs detected in blood differentiated WD patients from healthy and disease control subjects, and distinguished between patients with hepatic and neurologic WD manifestations. WD phenotype DMRs corresponded to genes enriched for functions in mental deterioration, abnormal B cell physiology, and as members of the polycomb repressive complex 1 (PRC1). 44 DMRs associated with WD phenotype tested in a small validation cohort had a predictive value of 0.9.ConclusionsWe identified a disease-mechanism relevant epigenomic signature of WD that reveals new insights into potential biomarkers and treatments for this complex monogenic disease.
| S-EPMC6357467 | biostudies-literature
Project description:Diagnosis of Wilson disease (WD) can be difficult because of its protean clinical presentation, but early diagnosis is important because effective treatment is available and can prevent disease progression. Using quantitative proteomics, we characterized proteins that are differentially expressed in WD compared to normal liver. Further the expression of MT1M and COX17 were validated using immunohistochemistry. We found diffuse MT immunoreactivity in all liver specimens from patients with WD (n=20), the intensity of the staining was moderate to strong. This staining pattern was distinct from that seen in specimens from the control groups which included diseases that may be in the clinical or histologic differential of WD (steatohepatitis (n=51), chronic viral hepatitis (n=40), autoimmune hepatitis (n=50), chronic biliary tract disease (n=42), and normal liver (n=20)). COX17 immunostain showed no significant difference in expression between the WD and control groups. MT had higher sensitivity than rhodanine for diagnosis of WD. While the quantitative liver copper assays also had high sensitivity, they require more tissue, have a higher cost, have longer turnaround time, and are less widely available than an immunohistochemical stain. We conclude that MT IHC is a sensitive immunohistochemical stain for the diagnosis of Wilson disease that could be widely deployed as a screening tool for liver biopsies in which Wilson disease is in the clinical or histologic differential diagnosis.
2023-04-18 | PXD029069 | Pride
Project description:Wilson disease (WD) is a severe metabolic disorder caused by genetic inactivation of copper-transporting ATPase ATP7B. In WD, copper accumulates in several tissues, particularly in the liver, inducing marked time-dependent pathological changes. To identify initial events in the copper-dependent development of liver pathology we utilized the Atp7b-/- mice, an animal model for WD. Analysis of mRNA from livers of control and Atp7b-/- 6 weeks-old mice using oligonucleotide arrays revealed specific changes of the transcriptome at this stage of copper accumulation. Few messages (29 up-regulated and 46 down-regulated) change their abundance more than 2-fold pointing to the specific effect of copper on gene expression/mRNA stability. The gene ontology analysis revealed copper effects on distinct metabolic pathways. Keywords: comparative genomic hybridization
2006-12-19 | GSE5348 | GEO
Project description:INCLUDE: Human Trisome Project
| PRJNA854739 | ENA
Project description:INCLUDE: Human Trisome Project
| PRJNA854738 | ENA
Project description:Wilson disease (WD) is a severe metabolic disorder caused by genetic inactivation of copper-transporting ATPase ATP7B. In WD, copper accumulates in several tissues, particularly in the liver, inducing marked time-dependent pathological changes. To identify initial events in the copper-dependent development of liver pathology we utilized the Atp7b-/- mice, an animal model for WD. Analysis of mRNA from livers of control and Atp7b-/- 6 weeks-old mice using oligonucleotide arrays revealed specific changes of the transcriptome at this stage of copper accumulation. Few messages (29 up-regulated and 46 down-regulated) change their abundance more than 2-fold pointing to the specific effect of copper on gene expression/mRNA stability. The gene ontology analysis revealed copper effects on distinct metabolic pathways. Experiment Overall Design: RNA isolation for microarrays: Immediately after removal, what size [mg] the liver pieces for RNA isolation were frozen in liquid nitrogen and stored till further use. The total RNA was isolated from frozen mouse livers using TRIZOL reagent (Invitrogen) according to manufacturerâs recommendations followed by a subsequent sample
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Project description:Transcriptomic changes in human liver cancer cell lines caused by the demethylating drug zebularine. Epigenomic changes such as aberrant hypermethylation and subsequent atypical gene silencing are characteristic features of human cancer. Here, we report a comprehensive characterization of epigenomic modulation caused by zebularine, an effective DNA methylation inhibitor, in human liver cancer. Using transcriptomic and epigenomic profiling, we identified a zebularine signature that classified liver cancer cell lines into two major subtypes with different drug-responses. In drug-sensitive cell lines, zebularine caused inhibition of proliferation coupled with increased apoptosis, whereas drug-resistant cell lines were associated with upregulation of oncogenic networks (e.g. E2F1, MYC, and TNF) driving liver cancer growth in vitro and in mice. Assessment of zebularine-based therapy in xenograft mouse models demonstrated potent therapeutic effects against tumors established from zebularine-sensitive but not zebularine-resistant liver cancer cells leading to increased survival and decreased pulmonary metastasis. Integration of zebularine gene expression and demethylation response signatures differentiated patients with HCC according to their survival and disease recurrence and identified a subclass of patients within the poor survivors likely to benefit from therapeutic agents that target the cancer epigenome. Each cell line was mock treated or treated with 100uM and 200uM zebularine for 7 days, respectively *** This Series represents the gene expression component of the study.
2011-07-30 | E-GEOD-23991 | biostudies-arrayexpress
Project description:Epigenetic dysregulation is a universal feature of cancer that results in altered patterns of gene expression that drive malignancy. Brain tumors exhibit subtype-specific epigenetic alterations, however the molecular mechanisms responsible for these diverse epigenetic states remain unclear. Here we show that the developmental transcription factor Sox9 differentially regulates epigenomic states in high-grade glioma (HGG) and ependymoma (EPN). These contrasting roles for Sox9 correspond with protein interactions with histone deacetylating complexes in HGG, and association with the Rela oncofusion in EPN. Together, our studies demonstrate how epigenomic states are differentially regulated in distinct subtypes of brain tumors, while revealing divergent roles for Sox9 in HGG and EPN tumorigenesis.
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