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Hum Mol Genet. 2018 Nov 15;27(22):3854-3869. doi: 10.1093/hmg/ddy262.

Epigenetic changes of the thioredoxin system in the tx-j mouse model and in patients with Wilson disease.

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Department of Medical Microbiology and Immunology, Genome Center, and MIND Institute, University of California, Davis, California, USA.
Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California, Davis, California, USA.
Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland.
Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany.
Department of Pathology, University of California, Davis, California, USA.
California Pacific Medical Center, San Francisco, California, USA.
Department of Surgery, University of California, Davis, California, USA.


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 (TNX1) 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 TXN1 and peroxiredoxin 1 (Prdx1) were significantly higher in mice receiving maternal and continued choline with or without PCA treatment compared to untreated mice. A WGBS comparison of human WD liver and tx-j mouse liver demonstrated a significant overlap of differentially methylated genes associated with ATP7B deficiency. Further, eight genes in the thioredoxin (TXN) pathway were differentially methylated in human WD liver samples. In summary, Atp7b deficiency and choline supplementation have a genome-wide impact, including on TXN system-related genes, in tx-j mice. These findings could explain the variability of WD phenotype and suggest new complementary treatment options for WD.

[Available on 2019-11-15]
[Indexed for MEDLINE]

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