TY - JOUR
T1 - Methyl deficiency causes reduction of the methyl-CpG-binding protein, MeCP2, in rat liver
AU - Esfandiari, Farah
AU - Green, Ralph
AU - Cotterman, Rebecca F.
AU - Pogribny, Igor P.
AU - James, S. Jill
AU - Miller, Joshua W.
N1 - Funding Information:
We thank Janine M.Lasalle, PhD, Assistant Professor, University of California Davis, School of Medicine, Department of Medical Microbiology and Immunology, for critical reading of the manuscript. We thank I-Ting Yu, MD, University of California Davis, Department of Medical Pathology for the liver section staining and morphological assessments. This study was financially supported by the American Institute for Cancer Research, Washington, DC (grant #01A034-REV), and was presented in part at the 2002 Experimental Biology (FASEB J., 2002, 16, A264.) and American Association for Cancer Research (Proc. Am. Assoc. Cancer Res., 2002, 43, 1125) annual meetings.
PY - 2003/12
Y1 - 2003/12
N2 - MeCP2 is a member of a family of proteins [methyl-(cytosine-guanine)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 2-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 co-repressor protein, Sin3a, at 36 weeks. Moreover, a known gene target of MeCP2, the tumor suppressor gene metallothionein-I, was over-expressed 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 pre-neoplastic change.
AB - MeCP2 is a member of a family of proteins [methyl-(cytosine-guanine)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 2-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 co-repressor protein, Sin3a, at 36 weeks. Moreover, a known gene target of MeCP2, the tumor suppressor gene metallothionein-I, was over-expressed 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 pre-neoplastic change.
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U2 - 10.1093/carcin/bgg163
DO - 10.1093/carcin/bgg163
M3 - Article
C2 - 12949043
AN - SCOPUS:0348149136
SN - 0143-3334
VL - 24
SP - 1935
EP - 1940
JO - Carcinogenesis
JF - Carcinogenesis
IS - 12
ER -