title: Periconceptional folate consumption is associated with neonatal DNA methylation modifications in neural crest regulatory and cancer development genes.
abstract: Folate deficiency during early embryonic development constitutes a risk factor for neural tube defects and potentially for childhood leukemia via unknown mechanisms. We tested whether folate consumption during the 12 months prior to conception induced DNA methylation modifications at birth in healthy neonates with a genome-wide and agnostic approach. We hypothesized that DNA methylation in genes involved in neural tube development and/or cancer susceptibility would be affected by folate exposure. We retrospectively assessed folate exposure at the time of conception by food-frequency questionnaires administered to the mothers of 343 healthy newborns. We measured genome-wide DNA methylation from neonatal blood spots. We implemented a method based on bootstrap resampling to decrease false-positive findings. Folate was inversely associated with DNA methylation throughout the genome. Among the top folate-associated genes that were replicated in an independent Gambian study were TFAP2A, a gene critical for neural crest development, STX11, a gene implicated in acute myeloid leukemia, and CYS1, a candidate gene for cystic kidney disease. Reduced periconceptional folate intake was associated with increased methylation and, in turn, decreased gene expression at these 3 loci. The top folate-sensitive genes defined by their associated CpG sites were enriched for numerous transcription factors by Gene Set Enrichment Analysis, including those implicated in cancer development (e.g., MYC-associated zinc finger protein). The influence of estimated periconceptional folate intake on neonatal DNA methylation levels provides potential mechanistic insights into the role of this vitamin in the development of neural tube defects and childhood cancers.
authors.affiliation: a Department of Epidemiology and Biostatistics ; Laboratory for Molecular Epidemiology; University of California ; San Francisco , CA , USA.
authors.forename: Semira
authors.initials: S
authors.lastname: Gonseth
authors.affiliation: b Computational Biology Core; HDF Comprehensive Cancer Center; University of California ; San Francisco , CA , USA.
authors.forename: Ritu
authors.initials: R
authors.lastname: Roy
authors.affiliation: c College of Public Health and Human Sciences; Oregon State University ; Corvallis , OR , USA.
authors.forename: E Andres
authors.initials: EA
authors.lastname: Houseman
authors.affiliation: a Department of Epidemiology and Biostatistics ; Laboratory for Molecular Epidemiology; University of California ; San Francisco , CA , USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: de Smith
authors.affiliation: a Department of Epidemiology and Biostatistics ; Laboratory for Molecular Epidemiology; University of California ; San Francisco , CA , USA.
authors.forename: Mi
authors.initials: M
authors.lastname: Zhou
authors.affiliation: d Department of Laboratory Medicine ; Yonsei University College of Medicine ; Seoul , Republic of Korea.
authors.forename: Seung-Tae
authors.initials: ST
authors.lastname: Lee
authors.affiliation: e Department of Environmental Science ; Policy & Management; University of California ; Berkeley , CA , USA.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Nusslé
authors.affiliation: f School of Public Health; University of California ; Berkeley , CA , USA.
authors.forename: Amanda W
authors.initials: AW
authors.lastname: Singer
authors.affiliation: g Department of Neurological Surgery ; University of California ; San Francisco , CA , USA.
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Wrensch
authors.affiliation: f School of Public Health; University of California ; Berkeley , CA , USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Metayer
authors.affiliation: a Department of Epidemiology and Biostatistics ; Laboratory for Molecular Epidemiology; University of California ; San Francisco , CA , USA.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Wiemels
mesh_terms: D019175:DNA Methylation; D019587:Dietary Supplements; D057890:Epigenomics; D005260:Female; D005306:Fertilization; D005492:Folic Acid / Q000494:pharmacology*; D005494:Folic Acid Deficiency / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D052138:Genes, Neoplasm; D006801:Humans; D007231:Infant, Newborn; D008565:Membrane Proteins / Q000235:genetics; D009432:Neural Crest / Q000196:embryology* / Q000378:metabolism; D009436:Neural Tube Defects / Q000235:genetics; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D050765:Qa-SNARE Proteins / Q000235:genetics; D012189:Retrospective Studies; D013997:Time Factors; D050656:Transcription Factor AP-2 / Q000235:genetics
chemical_list: C482294:CYS1 protein, human; D008565:Membrane Proteins; D050765:Qa-SNARE Proteins; C541732:STX11 protein, human; C493673:TFAP2A protein, human; D050656:Transcription Factor AP-2; D005492:Folic Acid
keywords: DNA methylation; cancer prevention; developmental origin of health and disease; epigenetics; folate; neural tube defects