TY - JOUR
T1 - Epigenetic alterations in the brains of Fisher 344 rats induced by long-term administration of folate/methyl-deficient diet
AU - Pogribny, Igor P.
AU - Karpf, Adam R.
AU - James, Smitha R.
AU - Melnyk, Stepan
AU - Han, Tao
AU - Tryndyak, Volodymyr P.
PY - 2008/10/27
Y1 - 2008/10/27
N2 - The maintenance of the cellular epigenomic landscape, which depends on the status of the one-carbon metabolic pathway, is essential for normal central nervous system development and function. In the present study, we examined the epigenetic alterations in the brains of Fisher 344 rats induced by the long-term administration of a diet lacking of essential one-carbon nutrients, methionine, choline, and folic acid. The results demonstrated that feeding a folate/methyl-deficient diet causes global DNA hypermethylation as indicated by an increase of genomic 5-methyl-2′-deoxycytidine (5mdC) content and more importantly, by an increase of methylation within unmethylated CpG-rich DNA domains. Interestingly, these epigenetic changes were opposite to those observed in the livers of the same folate/methyl-deficient rats. The hypermethylation changes were associated with an increased protein expression of de novo DNA methyltransferase DNMT3a and methyl-CpG-binding protein 2. Additionally, the gene expression profiling identified 33 significantly up- or down-regulated genes (fold change ≥ 1.5 and p ≤ 0.05) in the brains of rats fed a folate/methyl-deficient diet for 36 weeks. Interestingly, we detected an up-regulation of regulatory factor X, 3 (Rfx3) gene, a sequence-specific DNA-binding protein, that mediates the transcriptional activation of silenced by methylation genes, which may be an adaptive protective brain response to hypermethylation. Together, these data suggest that the proper maintenance of the epigenomic landscape in normal brain depends on the adequate supply of essential nutrients involved in the metabolism of methyl groups.
AB - The maintenance of the cellular epigenomic landscape, which depends on the status of the one-carbon metabolic pathway, is essential for normal central nervous system development and function. In the present study, we examined the epigenetic alterations in the brains of Fisher 344 rats induced by the long-term administration of a diet lacking of essential one-carbon nutrients, methionine, choline, and folic acid. The results demonstrated that feeding a folate/methyl-deficient diet causes global DNA hypermethylation as indicated by an increase of genomic 5-methyl-2′-deoxycytidine (5mdC) content and more importantly, by an increase of methylation within unmethylated CpG-rich DNA domains. Interestingly, these epigenetic changes were opposite to those observed in the livers of the same folate/methyl-deficient rats. The hypermethylation changes were associated with an increased protein expression of de novo DNA methyltransferase DNMT3a and methyl-CpG-binding protein 2. Additionally, the gene expression profiling identified 33 significantly up- or down-regulated genes (fold change ≥ 1.5 and p ≤ 0.05) in the brains of rats fed a folate/methyl-deficient diet for 36 weeks. Interestingly, we detected an up-regulation of regulatory factor X, 3 (Rfx3) gene, a sequence-specific DNA-binding protein, that mediates the transcriptional activation of silenced by methylation genes, which may be an adaptive protective brain response to hypermethylation. Together, these data suggest that the proper maintenance of the epigenomic landscape in normal brain depends on the adequate supply of essential nutrients involved in the metabolism of methyl groups.
KW - Brain
KW - DNA methylation
KW - Epigenetics
KW - Folate/methyl-deficient diet
KW - Gene expression
KW - Rat
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U2 - 10.1016/j.brainres.2008.07.077
DO - 10.1016/j.brainres.2008.07.077
M3 - Article
C2 - 18694733
AN - SCOPUS:53149144633
SN - 0006-8993
VL - 1237
SP - 25
EP - 34
JO - Brain Research
JF - Brain Research
ER -