Epigenetic alterations in folate transport genes in placental tissue from fetuses with neural tube defects and in leukocytes from subjects with hyperhomocysteinemia

Abstract

The objectives of this study were to identify tissue-specific differentially methylated regions (T-DMR’s) in the folate transport genes in placental tissue compared with leukocytes, and from placental tissues obtained from normal infants or with neural tube defects (NTDs). Using pyrosequencing, we developed methylation assays for the CpG islands (CGIs) and the CGI shore regions of the folate receptor α (FOLR1), proton-coupled folate transporter (PCFT) and reduced folate carrier 1 (RFC1) genes. The T-DMRs differed in location for each gene and the difference in methylation ranged between 2 and 54%. A higher T-DMR methylated fraction was associated with a lower mRNA level of the FOLR1 and RFC1 genes. Methylation fractions differed according to RFC1 80G > A genotype in the NTD cases and in leukocytes from subjects with high total plasma homocysteine (tHcy). There were no differences in methylated fraction of folate transporter genes between NTD cases and controls. We suggest that T-DMRs participate in the regulation of expression of the FOLR1 and RFC1 genes, that the RFC1 80G > A polymorphism exerts a gene-nutrition interaction on DNA methylation in the RFC1 gene, and that this interaction appears to be most prominent in NTD-affected births and in subjects with high tHcy concentrations.

Keywords: :

• FOLR1
• PCFT
• RFC1 80G>A
• homocysteine
• tissue-specific DNA methylation
• GpG island
• NTD

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

Financial support by Lions cancerfond, Nyckelfonden, and Örebro läns landsting is gratefully acknowledged. RHF was supported in part by NIH grants HD067244 and ES021390. AR was supported in part by a grant from the State Key Development Program for Basic Research (2007CB5119001), People’s Republic of China.

Financial Disclosures

S.A.F., A.K.B., H.S.I. and T.K.N. were supported by Lions cancerfond, Nyckelfonden and Örebro läns landsting. RHF was supported in part by NIH grants HD067244 and ES021390. A.R. was supported in part by a grant from the State Key Development Program for Basic Research (2007CB5119001), People’s Republic of China.