Maternal choline modifies fetal liver copper, gene expression, DNA methylation, and neonatal growth in the tx-j mouse model of Wilson disease

Abstract

Maternal diet can affect fetal gene expression through epigenetic mechanisms. Wilson disease (WD), which is caused by autosomal recessive mutations in ATP7B encoding a biliary copper transporter, is characterized by excessive hepatic copper accumulation, but variability in disease severity. We tested the hypothesis that gestational supply of dietary methyl groups modifies fetal DNA methylation and expression of genes involved in methionine and lipid metabolism that are impaired prior to hepatic steatosis in the toxic milk (tx-j) mouse model of WD. Female C3H control and tx-j mice were fed control (choline 8 mmol/Kg of diet) or choline-supplemented (choline 36 mmol/Kg of diet) diets for 2 weeks throughout mating and pregnancy to gestation day 17. A second group of C3H females, half of which were used to cross foster tx-j pups, received the same diet treatments that extended during lactation to 21 d postpartum. Compared with C3H, fetal tx-j livers had significantly lower copper concentrations and significantly lower transcript levels of Cyclin D1 and genes related to methionine and lipid metabolism. Maternal choline supplementation prevented the transcriptional deficits in fetal tx-j liver for multiple genes related to cell growth and metabolism. Global DNA methylation was increased by 17% in tx-j fetal livers after maternal choline treatment (P<0.05). Maternal dietary choline rescued the lower body weight of 21 d tx-j mice. Our results suggest that WD pathogenesis is modified by maternal in utero factors, including dietary choline.

Wilson disease: At the crossroads between genetics and epigenetics—A review of the evidence

“…Betaine supplementation increases SAM and Dnmt3b levels and restores DNA methylation in the liver. 104 Our group found a 17% rise in global DNA methylation, concurrent with changes in fetal hepatic gene expression, in fetal tx-j mice from dams that received choline-supplemented diets versus adequate choline in their diets; 105 notably, fetal liver bred from homozygous tx-j dams exhibited copper deficiency—not excess levels. 105 Mice that are born to homozygous tx-j dams might be a useful model for studying copper deficiency-induced fatty liver.…”

“…104 Our group found a 17% rise in global DNA methylation, concurrent with changes in fetal hepatic gene expression, in fetal tx-j mice from dams that received choline-supplemented diets versus adequate choline in their diets; 105 notably, fetal liver bred from homozygous tx-j dams exhibited copper deficiency—not excess levels. 105 Mice that are born to homozygous tx-j dams might be a useful model for studying copper deficiency-induced fatty liver. 110 These data indicate that hepatic copper accumulation alters DNA methylation in a mouse model of WD whereas dietary intervention with methyl donors restoresit.…”

“…101 Animal studies in the Jackson toxic milk (tx-j) mouse model of WD support this model, 102 astx-j mice show DNA hypomethylation and altered expression of genes that are involved in DNA methylation compared with wild-type mice. 103–105 Methylation reactions rely on the availability of the universal methyl donor S-adenosylmethionine (SAM), most of which is produced in the liver. 106 Methionine and ATP produce SAM via methionine adenosyltransferase (MAT).SAM is then converted to S-adenosylhomocysteine (SAH) through the bi-directional enzyme S-adenosylhomocysteine hydrolase (AHCY).ACHY is a key enzyme that regulates the amount of SAM that is available for methylation reactions.…”

Choline metabolites

“…A study using a toxic milk (tx-j) mouse model of Wilson’s Disease on a C3H/HeJ background found that maternal choline supplementation altered transcript levels of methionine and lipid metabolism genes. In this study, maternal choline supplementation increased global DNA methylation measured in fetal livers, indicating the importance of dietary choline during fetal development [23]. Additional studies have argued that the availability of methyl donors is tightly regulated, and that high levels of methylation are not universally protective as increased DNA methylation may be linked to behavioral disorders [24–26].…”

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