Analysis of DNA methylation and gene expression for thioredoxin system genes in Wilson disease
Article: Epigenetic changes of the thioredoxin system in the tx-j mouse model and in patients with Wilson disease
Mordaunt CE, Shibata NM, Kieffer DA, Czlonkowska A, Litwin T, Weiss KH, Gotthardt DN, Olson K, Wei D, Cooper S, Wan YJY, Ali M, LaSalle JM*, and Medici V*. 2019. Human Molecular Genetics 27(22):3854-3869.
Published Article: https://academic.oup.com/hmg/article/27/22/3854/5054134
Raw Data: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE117592
Wilson disease (WD) is caused by mutations in the copper transporter ATP7B, leading to copper accumulation in the liver and brain. Excess copper inhibits S-adenosyl-L-homocysteine hydrolase, leading to variable WD phenotypes from widespread alterations in DNA methylation and gene expression. Previously, we demonstrated that maternal choline supplementation in the Jackson toxic milk (tx-j) mouse model of WD corrected higher thioredoxin 1 transcript levels in fetal liver. Here, we investigated the effect of maternal choline supplementation on genome-wide DNA methylation patterns in tx-j fetal liver by whole-genome bisulfite sequencing (WGBS).
Tx-j Atp7b genotype-dependent differences in DNA methylation were corrected by choline for genes including, but not exclusive to, oxidative stress pathways. To examine phenotypic effects of postnatal choline supplementation, tx-j mice were randomized to one of six treatment groups: with or without maternal and/or continued choline supplementation, and with or without copper chelation with penicillamine (PCA) treatment. Hepatic transcript levels of thioredoxin 1 and peroxiredoxin 1 were significantly higher in mice receiving maternal and continued choline with or without PCA treatment compared to untreated mice. A comparison of WGBS of human WD liver compared to tx-j mouse liver demonstrated a significant overlap of differentially-methylated genes associated with ATP7B deficiency. Further, eight genes in the thioredoxin pathway were differentially methylated in human WD liver samples.
In summary, Atp7b deficiency and choline supplementation have a genome-wide impact, including on thioredoxin system-related genes, in tx-j mice. These findings could explain the variability of WD phenotype and suggest new complementary treatment options for WD.