Carcinogenesis Advance Access published online on August 29, 2003
Carcinogenesis, doi:10.1093/carcin/bgg163
© 2003 by Oxford University Press
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CARCINOGENESIS
1 University of California Davis, School of Medicine, Dept. of Medical Pathology, Sacramento, CA, 95817
* Corresponding author. E-mail: jwmiller{at}ucdavis.edu.
Received 31 October 2002
; revised 24 July 2003
; accepted 19 August 2003
MeCP2 is a member of a family of proteins (methyl-CpG-binding proteins) that bind specifically to methylated DNA and induce chromatin remodeling and gene silencing. Dietary deficiency of folate, choline, and methionine causes decreased tissue S-adenosylmethionine concentrations (methyl deficiency), global DNA hypomethylation, hepatic steatosis, cirrhosis and ultimately hepatic tumorigenesis in rodents. We investigated the effects of this diet on expression of MeCP2 during preneoplastic transformation of liver tissue. After 9 weeks, MeCP2 mRNA level was slightly higher in methyl-deficient rats compared with replete controls, while after 36 weeks, a difference in MeCP2 mRNA level was no longer observed. In contrast, MeCP2 protein level was reduced almost two-fold in the deficient rats compared with replete controls at both 9 and 36 weeks. Conversely, a second methyl-CpG-binding protein, MBD2, showed increased levels of both message and protein at the two time points. Low MeCP2 protein in the deficient rats was associated with a low level of the corepressor protein, Sin3a, at 36 weeks. Moreover, a known gene target of MeCP2, the tumor suppressor gene metallothionein-I, was overexpressed in the deficient rat livers at both 9 and 36 weeks, suggesting that reduction in MeCP2 may have functional consequences. Methyl deficiency also caused an increase in the ratio of long to short variants of MeCP2 transcripts. This finding suggests that reduced MeCP2 protein level is the result of a reduced rate of translation. Reduction of MeCP2 protein expression may influence the initiation and/or progression of hepatic cancer induced by methyl deficiency and may provide a useful marker of preneoplastic change.
Methyl-CpG-binding protein, MeCP2, MBD2, Sin3a, Metallothionein-1, Folate, Choline, Methionine, Methyl Deficiency
Methyl deficiency causes reduction of the methyl-CpG-binding protein, MeCP2, in rat liver
2 National Center for Toxicological Research, Dept. of Biochemical Toxicology, Jefferson, AR, 72079
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