Characterization of timed changes in hepatic copper concentrations, Methionine metabolism, gene expression, and global DNA Methylation in the Jackson toxic milk mouse model of Wilson disease

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

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Background: Wilson disease (WD) is characterized by hepatic copper accumulation with progressive liver damage to cirrhosis. This study aimed to characterize the toxic milk mouse from The Jackson Laboratory (Bar Harbor, ME, USA) (tx-j) mouse model of WD according to changes over time in hepatic copper concentrations, methionine metabolism, global DNA methylation, and gene expression from gestational day 17 (fetal) to adulthood (28 weeks). Methods: Included liver histology and relevant biochemical analyses including hepatic copper quantification, S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) liver levels, qPCR for transcript levels of genes relevant to methionine metabolism and liver damage, and DNA dot blot for global DNA methylation. Results: Hepatic copper was lower in tx-j fetuses but higher in weanling (three weeks) and adult tx-j mice compared to controls. S-adenosylhomocysteinase transcript levels were significantly lower at all time points, except at three weeks, correlating negatively with copper levels and with consequent changes in the SAM:SAH methylation ratio and global DNA methylation. Conclusion: Compared to controls, methionine metabolism including S-adenosylhomocysteinase gene expression is persistently different in the tx-j mice with consequent alterations in global DNA methylation in more advanced stages of liver disease. The inhibitory effect of copper accumulation on S-adenosylhomocysteinase expression is associated with progressively abnormal methionine metabolism and decreased methylation capacity and DNA global methylation.

Original languageEnglish (US)
Pages (from-to)8004-8023
Number of pages20
JournalInternational Journal of Molecular Sciences
Volume15
Issue number5
DOIs
StatePublished - May 7 2014

Fingerprint

methionine
Hepatolenticular Degeneration
methylation
milk
gene expression
Poisons
metabolism
DNA Methylation
Metabolism
Gene expression
Methionine
mice
Copper
Milk
Liver
Adenosylhomocysteinase
deoxyribonucleic acid
liver
Gene Expression
copper

Keywords

  • Copper
  • DNA
  • Gene expression
  • Methylation
  • Wilson disease

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Spectroscopy
  • Inorganic Chemistry
  • Catalysis
  • Molecular Biology
  • Computer Science Applications
  • Medicine(all)

Cite this

Characterization of timed changes in hepatic copper concentrations, Methionine metabolism, gene expression, and global DNA Methylation in the Jackson toxic milk mouse model of Wilson disease. / Le, Anh; Shibata, Noreene M.; French, Samuel W.; Kim, Kyoungmi; Kharbanda, Kusum K.; Islam, Mohammad S.; LaSalle, Janine M; Halsted, Charles H.; Keen, Carl L; Medici, Valentina.

In: International Journal of Molecular Sciences, Vol. 15, No. 5, 07.05.2014, p. 8004-8023.

Research output: Contribution to journalArticle

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title = "Characterization of timed changes in hepatic copper concentrations, Methionine metabolism, gene expression, and global DNA Methylation in the Jackson toxic milk mouse model of Wilson disease",
abstract = "Background: Wilson disease (WD) is characterized by hepatic copper accumulation with progressive liver damage to cirrhosis. This study aimed to characterize the toxic milk mouse from The Jackson Laboratory (Bar Harbor, ME, USA) (tx-j) mouse model of WD according to changes over time in hepatic copper concentrations, methionine metabolism, global DNA methylation, and gene expression from gestational day 17 (fetal) to adulthood (28 weeks). Methods: Included liver histology and relevant biochemical analyses including hepatic copper quantification, S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) liver levels, qPCR for transcript levels of genes relevant to methionine metabolism and liver damage, and DNA dot blot for global DNA methylation. Results: Hepatic copper was lower in tx-j fetuses but higher in weanling (three weeks) and adult tx-j mice compared to controls. S-adenosylhomocysteinase transcript levels were significantly lower at all time points, except at three weeks, correlating negatively with copper levels and with consequent changes in the SAM:SAH methylation ratio and global DNA methylation. Conclusion: Compared to controls, methionine metabolism including S-adenosylhomocysteinase gene expression is persistently different in the tx-j mice with consequent alterations in global DNA methylation in more advanced stages of liver disease. The inhibitory effect of copper accumulation on S-adenosylhomocysteinase expression is associated with progressively abnormal methionine metabolism and decreased methylation capacity and DNA global methylation.",
keywords = "Copper, DNA, Gene expression, Methylation, Wilson disease",
author = "Anh Le and Shibata, {Noreene M.} and French, {Samuel W.} and Kyoungmi Kim and Kharbanda, {Kusum K.} and Islam, {Mohammad S.} and LaSalle, {Janine M} and Halsted, {Charles H.} and Keen, {Carl L} and Valentina Medici",
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T1 - Characterization of timed changes in hepatic copper concentrations, Methionine metabolism, gene expression, and global DNA Methylation in the Jackson toxic milk mouse model of Wilson disease

AU - Le, Anh

AU - Shibata, Noreene M.

AU - French, Samuel W.

AU - Kim, Kyoungmi

AU - Kharbanda, Kusum K.

AU - Islam, Mohammad S.

AU - LaSalle, Janine M

AU - Halsted, Charles H.

AU - Keen, Carl L

AU - Medici, Valentina

PY - 2014/5/7

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N2 - Background: Wilson disease (WD) is characterized by hepatic copper accumulation with progressive liver damage to cirrhosis. This study aimed to characterize the toxic milk mouse from The Jackson Laboratory (Bar Harbor, ME, USA) (tx-j) mouse model of WD according to changes over time in hepatic copper concentrations, methionine metabolism, global DNA methylation, and gene expression from gestational day 17 (fetal) to adulthood (28 weeks). Methods: Included liver histology and relevant biochemical analyses including hepatic copper quantification, S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) liver levels, qPCR for transcript levels of genes relevant to methionine metabolism and liver damage, and DNA dot blot for global DNA methylation. Results: Hepatic copper was lower in tx-j fetuses but higher in weanling (three weeks) and adult tx-j mice compared to controls. S-adenosylhomocysteinase transcript levels were significantly lower at all time points, except at three weeks, correlating negatively with copper levels and with consequent changes in the SAM:SAH methylation ratio and global DNA methylation. Conclusion: Compared to controls, methionine metabolism including S-adenosylhomocysteinase gene expression is persistently different in the tx-j mice with consequent alterations in global DNA methylation in more advanced stages of liver disease. The inhibitory effect of copper accumulation on S-adenosylhomocysteinase expression is associated with progressively abnormal methionine metabolism and decreased methylation capacity and DNA global methylation.

AB - Background: Wilson disease (WD) is characterized by hepatic copper accumulation with progressive liver damage to cirrhosis. This study aimed to characterize the toxic milk mouse from The Jackson Laboratory (Bar Harbor, ME, USA) (tx-j) mouse model of WD according to changes over time in hepatic copper concentrations, methionine metabolism, global DNA methylation, and gene expression from gestational day 17 (fetal) to adulthood (28 weeks). Methods: Included liver histology and relevant biochemical analyses including hepatic copper quantification, S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) liver levels, qPCR for transcript levels of genes relevant to methionine metabolism and liver damage, and DNA dot blot for global DNA methylation. Results: Hepatic copper was lower in tx-j fetuses but higher in weanling (three weeks) and adult tx-j mice compared to controls. S-adenosylhomocysteinase transcript levels were significantly lower at all time points, except at three weeks, correlating negatively with copper levels and with consequent changes in the SAM:SAH methylation ratio and global DNA methylation. Conclusion: Compared to controls, methionine metabolism including S-adenosylhomocysteinase gene expression is persistently different in the tx-j mice with consequent alterations in global DNA methylation in more advanced stages of liver disease. The inhibitory effect of copper accumulation on S-adenosylhomocysteinase expression is associated with progressively abnormal methionine metabolism and decreased methylation capacity and DNA global methylation.

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KW - DNA

KW - Gene expression

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