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Series GSE117592 Query DataSets for GSE117592
Status Public on Jul 25, 2018
Title Epigenetic changes of the thioredoxin system in the tx-j mouse model and in patients with Wilson disease
Organism Mus musculus
Experiment type Methylation profiling by high throughput sequencing
Summary 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.
Overall design Investigation of DNA methylation with whole-genome bisulfite sequencing (WGBS) in liver from tx-j and C3H mice at E17, with and without maternal choline supplementation. Tx-j mice carry a homozygous Gly712Asp missense mutation in Atp7b. Dams were fed normal or high choline diet for 2 weeks before mating and through gestation. Tx-j pups were fostered by C3H dam with sam diet that gave birth on the same day. Fetal livers of pups from the same litter were pooled. Pooled liver samples: C3H + control diet (n=4), C3H + choline diet (n=4), tx-j + control diet (n=4), tx-j + choline diet (n=4)
Web link
Contributor(s) Mordaunt CE, LaSalle JM, Medici V
Citation(s) 30010856
NIH grant(s)
Grant ID Grant title Affiliation Name
R03 DK099427 Wilson Disease: Effect of High-Choline Feeding on Fetal and Offspring Mouse Liver UNIVERSITY OF CALIFORNIA DAVIS Valentina Medici
R01 DK104770 Epigenetic regulation of Wilson Disease UNIVERSITY OF CALIFORNIA DAVIS Valentina Medici
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 (1)
GPL13112 Illumina HiSeq 2000 (Mus musculus)
Samples (16)
GSM3304366 Liver_WT_control_1
GSM3304367 Liver_WT_control_2
GSM3304368 Liver_WT_control_3
BioProject PRJNA482607
SRA SRP154996

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE117592_RAW.tar 1.3 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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