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

Valentina Medici, Noreene M. Shibata, Kusum Kharbanda, Mohammad S. Islam, Carl L. Keen, Kyoungmi Kim, Brittany Tillman, Samuel W. French, Charles H. Halsted, Janine M. LaSalle

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish (US)
JournalEpigenetics
Volume9
Issue number2
DOIs
StatePublished - Jan 1 2014

Fingerprint

Hepatolenticular Degeneration
DNA Methylation
Choline
Copper
Mothers
Gene Expression
Diet
Liver
Growth
Lipid Metabolism
Methionine
bcl-1 Genes
Pregnancy
Poisons
Lactation
Epigenomics
Postpartum Period
Milk
Body Weight
Mutation

Keywords

  • Choline
  • Copper
  • CyclinD1
  • DNA methylation
  • Fetus
  • Liver
  • S-adenosylmethionine

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

Maternal choline modifies fetal liver copper, gene expression, DNA methylation, and neonatal growth in the tx-j mouse model of Wilson disease. / Medici, Valentina; Shibata, Noreene M.; Kharbanda, Kusum; Islam, Mohammad S.; Keen, Carl L.; Kim, Kyoungmi; Tillman, Brittany; French, Samuel W.; Halsted, Charles H.; LaSalle, Janine M.

In: Epigenetics, Vol. 9, No. 2, 01.01.2014.

Research output: Contribution to journalArticle

Medici, Valentina ; Shibata, Noreene M. ; Kharbanda, Kusum ; Islam, Mohammad S. ; Keen, Carl L. ; Kim, Kyoungmi ; Tillman, Brittany ; French, Samuel W. ; Halsted, Charles H. ; LaSalle, Janine M. / Maternal choline modifies fetal liver copper, gene expression, DNA methylation, and neonatal growth in the tx-j mouse model of Wilson disease. In: Epigenetics. 2014 ; Vol. 9, No. 2.
@article{c7daa6a2441046f4a3123d741eea10d5,
title = "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.",
keywords = "Choline, Copper, CyclinD1, DNA methylation, Fetus, Liver, S-adenosylmethionine",
author = "Valentina Medici and Shibata, {Noreene M.} and Kusum Kharbanda and Islam, {Mohammad S.} and Keen, {Carl L.} and Kyoungmi Kim and Brittany Tillman and French, {Samuel W.} and Halsted, {Charles H.} and LaSalle, {Janine M.}",
year = "2014",
month = "1",
day = "1",
doi = "10.4161/epi.27110",
language = "English (US)",
volume = "9",
journal = "Epigenetics",
issn = "1559-2294",
publisher = "Landes Bioscience",
number = "2",

}

TY - JOUR

T1 - Maternal choline modifies fetal liver copper, gene expression, DNA methylation, and neonatal growth in the tx-j mouse model of Wilson disease

AU - Medici, Valentina

AU - Shibata, Noreene M.

AU - Kharbanda, Kusum

AU - Islam, Mohammad S.

AU - Keen, Carl L.

AU - Kim, Kyoungmi

AU - Tillman, Brittany

AU - French, Samuel W.

AU - Halsted, Charles H.

AU - LaSalle, Janine M.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

KW - Choline

KW - Copper

KW - CyclinD1

KW - DNA methylation

KW - Fetus

KW - Liver

KW - S-adenosylmethionine

UR - http://www.scopus.com/inward/record.url?scp=84892572547&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84892572547&partnerID=8YFLogxK

U2 - 10.4161/epi.27110

DO - 10.4161/epi.27110

M3 - Article

C2 - 24220304

AN - SCOPUS:84892572547

VL - 9

JO - Epigenetics

JF - Epigenetics

SN - 1559-2294

IS - 2

ER -