Wilson Disease: Epigenetic effects of choline supplementation on phenotype and clinical course in a mouse model.
Wilson disease (WD), a genetic disorder affecting copper transport, is characterized by hepatic and neurological manifestations with variable and often unpredictable presentation. Global DNA methylation in liver was previously modified by dietary choline in tx-j mice, a spontaneous mutant model of WD. We therefore hypothesized that the WD phenotype and hepatic gene expression of tx-j offspring could be modified by maternal methyl supplementation during pregnancy. In an initial experiment, female tx-j mice or wild type mice were fed control or choline-supplemented diets 2 weeks prior to mating through embryonic day 17. Transcriptomic analysis (RNA-seq) on embryonic livers revealed tx-j-specific differences in genes related to oxidative phosphorylation, mitochondrial dysfunction, and the neurological disorders Huntington's disease and Alzheimer disease. Maternal choline supplementation restored the transcript levels of a subset of genes to wild type levels. In a separate experiment, a group of tx-j offspring continued to receive choline-supplemented or control diets, with or without the copper chelator penicillamine (PCA) for 12 weeks until 24 weeks of age. Combined choline supplementation and PCA treatment of 24-week-old tx-j mice was associated with increased liver transcript levels of methionine metabolism and oxidative phosphorylation-related genes. Sex differences in gene expression within each treatment group were also observed. These results demonstrate that the transcriptional changes in oxidative phosphorylation and methionine metabolism genes in WD that originate during fetal life are, in part, prevented by prenatal maternal choline supplementation, a finding with potential relevance to preventive treatments of WD.
a Department of Internal Medicine, Division of Gastroenterology and Hepatology , University of California Davis , CA , USA.
Valentina
V
Medici
a Department of Internal Medicine, Division of Gastroenterology and Hepatology , University of California Davis , CA , USA.
Dorothy A
DA
Kieffer
a Department of Internal Medicine, Division of Gastroenterology and Hepatology , University of California Davis , CA , USA.
Noreene M
NM
Shibata
b Department of Nutrition , University of California Davis , CA , USA.
Harpreet
H
Chima
c Department of Public Health Sciences, Division of Biostatistics , University of California Davis , CA , USA.
Kyoungmi
K
Kim
d Department of Animal Science , University of California Davis , CA , USA.
Angela
A
Canovas
d Department of Animal Science , University of California Davis , CA , USA.
Juan F
JF
Medrano
d Department of Animal Science , University of California Davis , CA , USA.
Alma D
AD
Islas-Trejo
e Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System , Omaha , NE , USA.
Kusum K
KK
Kharbanda
f Department of Pathology , University of California Davis , CA , USA.
Kristin
K
Olson
f Department of Pathology , University of California Davis , CA , USA.
Ruijun J
RJ
Su
g Department of Medical Microbiology and Immunology , Genome Center, and MIND Institute, University of California Davis , CA , USA.
Mohammad S
MS
Islam
a Department of Internal Medicine, Division of Gastroenterology and Hepatology , University of California Davis , CA , USA.
Raisa
R
Syed
b Department of Nutrition , University of California Davis , CA , USA.
Carl L
CL
Keen
h Department of Internal Medicine, Division of Cardiovascular Medicine , University of California Davis , CA , USA.
Amy Y
AY
Miller
h Department of Internal Medicine, Division of Cardiovascular Medicine , University of California Davis , CA , USA.
John C
JC
Rutledge
a Department of Internal Medicine, Division of Gastroenterology and Hepatology , University of California Davis , CA , USA.
Charles H
CH
Halsted
g Department of Medical Microbiology and Immunology , Genome Center, and MIND Institute, University of California Davis , CA , USA.
Janine M
JM
LaSalle
D000818:Animals; D002794:Choline / Q000008:administration & dosage / Q000378:metabolism; D003300:Copper / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics*; D019587:Dietary Supplements; D004195:Disease Models, Animal; D057890:Epigenomics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006527:Hepatolenticular Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008715:Methionine / Q000378:metabolism; D051379:Mice; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010396:Penicillamine / Q000008:administration & dosage; D011247:Pregnancy; D059467:Transcriptome / Q000235:genetics*
D003300:Copper; D008715:Methionine; D010396:Penicillamine; D002794:Choline
Copper; Wilson Disease; choline; mitochondria; oxidative phosphorylation; toxic-milk mouse