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Series GSE117593 Query DataSets for GSE117593
Status Public on Feb 14, 2019
Title Epigenomic signatures in liver and blood of Wilson disease patients include hypermethylation of liver-specific enhancers
Organism Homo sapiens
Experiment type Methylation profiling by high throughput sequencing
Summary 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.
Overall design Investigation of DNA methylation with whole-genome bisulfite sequencing (WGBS) in liver and blood samples from Wilson disease (WD), Non-alcoholic fatty liver disease (NAFLD), primary sclerosing cholangitis (PSC), and healthy control (HC) subjects. Liver biopsies: 10 WD, 5 NAFLD, 6 HC subjects. Whole blood: 40 WD, 10 NAFLD, 10 PSC, 12 HC subjects.
Web link
Contributor(s) Mordaunt CE, LaSalle JM, Medici V
Citation(s) 30709419
NIH grant(s)
Grant ID Grant title Affiliation Name
R01 DK104770 Epigenetic regulation of Wilson Disease UNIVERSITY OF CALIFORNIA DAVIS Valentina Medici
P01 ES011269 Project 2: Perinatal Epigenetic Signature of Environmental Exposure UNIVERSITY OF CALIFORNIA DAVIS Janine M LaSalle
Submission date Jul 24, 2018
Last update date Feb 03, 2020
Contact name Charles E Mordaunt
Organization name University of California, Davis
Department Medical Microbiology and Immunology
Lab LaSalle Lab
Street address 3318 Tupper Hall, One Shields Ave
City Davis
State/province CA
ZIP/Postal code 95616
Country USA
Platforms (2)
GPL11154 Illumina HiSeq 2000 (Homo sapiens)
GPL20301 Illumina HiSeq 4000 (Homo sapiens)
Samples (103)
GSM3304382 Liver_HC_01
GSM3304383 Liver_HC_02
GSM3304384 Liver_HC_03
BioProject PRJNA482624
SRA SRP155006

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Supplementary file Size Download File type/resource
GSE117593_RAW.tar 12.8 Gb (http)(custom) TAR (of BED)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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