Abstract
BackgroundPericonceptional folic acid (FA) supplementation not only reduces the incidence of neural tube defects, but also improves cognitive performances in offspring. However, the genes or pathways that are epigenetically regulated by FA in neurodevelopment were rarely reported.MethodsTo elucidate the underlying mechanism, the effect of FA on the methylation profiles in brain tissue of male rat offspring was assessed by methylated DNA immunoprecipitation chip. Differentially methylated genes (DMGs) and gene network analysis were identified using DAVID and KEGG pathway analysis.ResultsCompared with the folate-normal diet group, 1939 DMGs were identified in the folate-deficient diet group, and 1498 DMGs were identified in the folate-supplemented diet group, among which 298 DMGs were overlapped. The pathways associated with neurodevelopment and learning/memory abilities were differentially methylated in response to maternal FA intake during pregnancy, and there were some identical and distinctive potential mechanisms under FA deficiency or FA-supplemented conditions.ConclusionsIn conclusion, genes and pathways associated with neurodevelopment and learning/memory abilities were differentially methylated in male rat offspring in response to maternal FA deficiency or supplementation during pregnancy.
Highlights
Emerging evidence has indicated that early life nutrition influences brain development and exerts long-term consequences for memory abilities profoundly [1, 2]
Compared with the folic acid (FA)-N group, 1843 differential enrichment peaks (DEPs) were identified in the FA-deficient diet (FA-D) group (744 hypermethylated and 1099 hypomethylated), and 1406 DEPs were identified in the FA-supplemented diet (FA-S) group (738 hypermethylated and 668 hypomethylated)
Comparing the FA-D group with the folic acid-normal (FA-N) group (FAD/FA-N), there are 996, 438, and 433 DEPs located in High-CpG-density promoter (HCP), Intermediate-CpG-density promoter (ICP), and Low-CpG-density promoter (LCP), respectively, while there were 699, 392, and 337 DEPs located, representatively, in the HCP, ICP, and LCP in the FA-S group compared with the FAN group (FA-S/FA-N)
Summary
Emerging evidence has indicated that early life nutrition influences brain development and exerts long-term consequences for memory abilities profoundly [1, 2]. DNA methylation and histone modification are the most studied epigenetic modifications reprogrammed considerably in early embryonic development [9]. Epigenetic alterations are thought to module gene expression and silencing [10], and their dysregulation may contribute to numerous neurodevelopment disorders [11, 12]. A meta-analysis that included 1988 newborns from two European birth cohorts revealed that maternal plasma folate during pregnancy impacted epigenome-wide DNA methylation in the cord blood. Thereby DNA methylation modification may play critical roles in neurodevelopment and learning/memory ability in offspring. The genes or pathways that are epigenetically regulated by FA in neurodevelopment were rarely reported
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