Wilson Disease: Epigenetic effects of choline supplementation on phenotype and clinical course in a mouse model

Valentina Medici, Dorothy A. Kieffer, Noreene M. Shibata, Harpreet Chima, Kyoungmi Kim, Angela Canovas, Juan F. Medrano, Alma D. Islas-Trejo, Kusum Kharbanda, Kristin Olson, Ruijun J. Su, Mohammad S. Islam, Raisa Syed, Carl L. Keen, Amy Y. Miller, John C. Rutledge, Charles H. Halsted, Janine M. LaSalle

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)804-818
Number of pages15
JournalEpigenetics
Volume11
Issue number11
DOIs
StatePublished - Nov 1 2016

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Hepatolenticular Degeneration
Choline
Epigenomics
Phenotype
Oxidative Phosphorylation
Liver
Penicillamine
Mothers
Methionine
Genes
Copper
Diet
Gene Expression
Inborn Genetic Diseases
Huntington Disease
DNA Methylation
Chelating Agents
Neurologic Manifestations
Nervous System Diseases
Sex Characteristics

Keywords

  • Copper
  • Wilson Disease
  • choline
  • mitochondria
  • oxidative phosphorylation
  • toxic-milk mouse

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

Medici, V., Kieffer, D. A., Shibata, N. M., Chima, H., Kim, K., Canovas, A., ... LaSalle, J. M. (2016). Wilson Disease: Epigenetic effects of choline supplementation on phenotype and clinical course in a mouse model. Epigenetics, 11(11), 804-818. https://doi.org/10.1080/15592294.2016.1231289

Wilson Disease : Epigenetic effects of choline supplementation on phenotype and clinical course in a mouse model. / Medici, Valentina; Kieffer, Dorothy A.; Shibata, Noreene M.; Chima, Harpreet; Kim, Kyoungmi; Canovas, Angela; Medrano, Juan F.; Islas-Trejo, Alma D.; Kharbanda, Kusum; Olson, Kristin; Su, Ruijun J.; Islam, Mohammad S.; Syed, Raisa; Keen, Carl L.; Miller, Amy Y.; Rutledge, John C.; Halsted, Charles H.; LaSalle, Janine M.

In: Epigenetics, Vol. 11, No. 11, 01.11.2016, p. 804-818.

Research output: Contribution to journalArticle

Medici, V, Kieffer, DA, Shibata, NM, Chima, H, Kim, K, Canovas, A, Medrano, JF, Islas-Trejo, AD, Kharbanda, K, Olson, K, Su, RJ, Islam, MS, Syed, R, Keen, CL, Miller, AY, Rutledge, JC, Halsted, CH & LaSalle, JM 2016, 'Wilson Disease: Epigenetic effects of choline supplementation on phenotype and clinical course in a mouse model', Epigenetics, vol. 11, no. 11, pp. 804-818. https://doi.org/10.1080/15592294.2016.1231289
Medici, Valentina ; Kieffer, Dorothy A. ; Shibata, Noreene M. ; Chima, Harpreet ; Kim, Kyoungmi ; Canovas, Angela ; Medrano, Juan F. ; Islas-Trejo, Alma D. ; Kharbanda, Kusum ; Olson, Kristin ; Su, Ruijun J. ; Islam, Mohammad S. ; Syed, Raisa ; Keen, Carl L. ; Miller, Amy Y. ; Rutledge, John C. ; Halsted, Charles H. ; LaSalle, Janine M. / Wilson Disease : Epigenetic effects of choline supplementation on phenotype and clinical course in a mouse model. In: Epigenetics. 2016 ; Vol. 11, No. 11. pp. 804-818.
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