Nutri-epigenomic Studies Related to Neural Tube Defects: Does Folate Affect Neural Tube Closure Via Changes in DNA Methylation?
Neural tube defects (NTDs), affecting 1-2 per 1000 pregnancies, are severe congenital malformations that arise from the failure of neurulation during early embryonic development. The methylation hypothesis suggests that folate prevents NTDs by stimulating cellular methylation reactions. Folate is central to the one-carbon metabolism that produces pyrimidines and purines for DNA synthesis and for the generation of the methyldonor S-adenosyl-methionine. This review focuses on the relation between the folate-mediated one-carbon metabolism, DNA methylation and NTDs. Studies will be discussed that investigated global or locus-specific DNA methylation differences in patients with NTDs. Folate deficiency may increase NTD risk by decreasing DNA methylation, but to date, human studies vary widely in study design in terms of analyzing different clinical subtypes of NTDs, using different methylation quantification assays and using DNA isolated from diverse types of tissues. Some studies have focused mainly on global DNA methylation differences while others have quantified specific methylation differences for imprinted genes, transposable elements and DNA repair enzymes. Findings of global DNA hypomethylation and LINE-1 hypomethylation suggest that epigenetic alterations may disrupt neural tube closure. However, current research does not support a linear relation between red blood cell folate concentration and DNA methylation. Further studies are required to better understand the interaction between folate, DNA methylation changes and NTDs.
Anne
A
Rochtus
Katrien
K
Jansen
Chris
C
Van Geet
Center for Molecular and Vascular Biology, University of Leuven, Campus Gasthuisberg, O&N1, Herestraat 49, Box 911, 3000 Leuven, Belgium. kathleen.freson@med.kuleuven.be.
Kathleen
K
Freson
D000818:Animals; D019175:DNA Methylation; D004032:Diet; D044127:Epigenesis, Genetic; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D005494:Folic Acid Deficiency / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D009436:Neural Tube Defects / Q000209:etiology / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D054647:Nutrigenomics; D011247:Pregnancy
D005492:Folic Acid