Analysis scripts for identification and visualization of Wilson disease-associated DNA methylation changes in human liver and blood.
Article: Epigenomic signatures in liver and blood of Wilson disease patients include hypermethylation of liver-specific enhancers
Mordaunt CE, Kieffer DA, Shibata NM, Czlonkowska A, Litwin T, Weiss KH, Zhu Y, Bowlus CL, Sarkar S, Cooper S, Wan YY, Ali M, LaSalle JM, and Medici V. 2019. Epigenetics & Chromatin 12(10):1-16.
Published Article: https://epigeneticsandchromatin.biomedcentral.com/articles/10.1186/s13072-019-0255-z
Raw Data: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE117593
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.
We used whole-genome bisulfite sequencing (WGBS) to examine distinct cohorts of WD subjects to determine if DNA methylation could differentiate patients from healthy subjects and subjects with other liver diseases. 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-hypermethyled 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 detected in blood differentiated WD patients from healthy and disease control subjects, and distinguished between patients with hepatic and neurologic WD manifestations. 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 genetic disease.