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.

Folate transporter expression in placenta from pregnancies complicated with birth defects

“…Information on regulation of folate transporter expression in human placental tissue is scarce. Farkas et al () investigated the epigenetic alterations of folate transport genes in placentas from fetuses with NTD. Although they did not observe differences in DNA methylation compared to those from healthy deliveries, they identified an interaction between homocystein levels (as a marker of folate nutritional status) and a RFC1 gene polymorphism (Farkas et al, ).…”

Genome-wide DNA methylation assay reveals novel candidate biomarker genes in cervical cancer

“…The PCR program was as follows: initial denaturation step of 1 min at 95 °C, followed by 45 cycles of 30 s denaturation at 95 °C, specific annealing T a for 30 s and extension for 30 s at 72 °C and one cycle of final extension for 30 s at 72 °C. Sequencing was performed using a Pyromark Gold Q96 Reagent Kit and a PSQ 96ID system (Qiagen) as described previously by Farkas et al 49 The nucleotide addition order was optimized by the Pyro Q-CpG software version 1.0.9 (Qiagen) and the results were automatically analyzed using the same software.…”

Sonic Hedgehog Signaling Affected by Promoter Hypermethylation Induces Aberrant Gli2 Expression in Spina Bifida

“…For instance, folate is integral to the intracellular one-carbon metabolism used in DNA methylation and a proportion of NTDs were shown to be prevented by folic acid supplementation [9]. Moreover, a study by Farkas et al suggested that a gene-nutrition interaction between folate intake, DNA methylation alternations in folate transport genes, and genotypes partly accounted for NTD births [10]. We also observed aberrant DNA methylation in Xiao-Lin Lu and Li Wang contributed equally to this work.…”