title: 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.
authors: Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden. sanja.farkas@orebroll.se
authors: Sanja A
authors: SA
authors: Farkas
authors: Anna K
authors: AK
authors: Böttiger
authors: Helena S
authors: HS
authors: Isaksson
authors: Richard H
authors: RH
authors: Finnell
authors: Aiguo
authors: A
authors: Ren
authors: Torbjörn K
authors: TK
authors: Nilsson
mesh_terms: D016022:Case-Control Studies; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D058975:Folate Receptor 1 / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D006710:Homocysteine / Q000097:blood; D006801:Humans; D020138:Hyperhomocysteinemia / Q000235:genetics* / Q000378:metabolism; D007231:Infant, Newborn; D007962:Leukocytes / Q000378:metabolism*; D009436:Neural Tube Defects / Q000235:genetics* / Q000378:metabolism; D010920:Placenta / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D058979:Proton-Coupled Folate Transporter / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051818:Replication Protein C / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C548696:FOLR1 protein, human; D058975:Folate Receptor 1; D058979:Proton-Coupled Folate Transporter; C081632:RFC1 protein, human; D012333:RNA, Messenger; C505058:SLC46A1 protein, human; D006710:Homocysteine; D051818:Replication Protein C
keywords: FOLR1; GpG island; NTD; PCFT; RFC180G>A; homocysteine; tissue-specific DNA methylation