Candidate genes linking maternal nutrient exposure to offspring health via DNA methylation: a review of existing evidence in humans with specific focus on one-carbon metabolism

Abstract

BackgroundMounting evidence suggests that nutritional exposures during pregnancy influence the fetal epigenome, and that these epigenetic changes can persist postnatally, with implications for disease risk across the life course.MethodsWe review human intergenerational studies using a three-part search strategy. Search 1 investigates associations between preconceptional or pregnancy nutritional exposures, focusing on one-carbon metabolism, and offspring DNA methylation. Search 2 considers associations between offspring DNA methylation at genes found in the first search and growth-related, cardiometabolic and cognitive outcomes. Search 3 isolates those studies explicitly linking maternal nutritional exposure to offspring phenotype via DNA methylation. Finally, we compile all candidate genes and regions of interest identified in the searches and describe their genomic locations, annotations and coverage on the Illumina Infinium Methylation beadchip arrays.ResultsWe summarize findings from the 34 studies found in the first search, the 31 studies found in the second search and the eight studies found in the third search. We provide details of all regions of interest within 45 genes captured by this review.ConclusionsMany studies have investigated imprinted genes as priority loci, but with the adoption of microarray-based platforms other candidate genes and gene classes are now emerging. Despite a wealth of information, the current literature is characterized by heterogeneous exposures and outcomes, and mostly comprise observational associations that are frequently underpowered. The synthesis of current knowledge provided by this review identifies research needs on the pathway to developing possible early life interventions to optimize lifelong health.

Maternal One-Carbon Metabolism and Infant DNA Methylation between Contrasting Seasonal Environments: A Case Study from The Gambia

“…Increased maternal periconceptional folate status has been associated with increased methylation in infants at a differentially methylated region of retinoid X receptor alpha ( RXRA ) (62). However, this pattern is not consistent, and inverse associations between fetal periconceptional folate exposure and methylation have also been found at syntaxin 11 ( STX11 ), orthodenticle homeobox 2 ( OTX2 ), transcription factor AP-2 alpha ( TFAP2A ), cystin 1 ( CYS1 ), and leptin ( LEP ) (39, 62, 63) .…”

“…In humans, there is also evidence linking maternal nutrition to offspring DNA methylation, explored either as individual micronutrients or as proxy measures of nutrition such as famine and seasonality (36, 37). Although there is also much evidence linking DNA methylation to later phenotype (12, 38), studies fully exploring the continuum of maternal nutrient exposure, offspring DNA methylation, and later phenotype are relatively rare (39).…”

DNA methylation changes related to nutritional deprivation: a genome-wide analysis of population and in vitro data

“…Replication of our findings in the Dutch famine [8] study was not possible due to the fact that these loci were eliminated in their analysis based on a low variance in whole-genome bisulphite sequencing data. Also, lookup of the presented DMRs in the studies of James et al [53] and Finer et al [4] did not identify an overlap. However, considering these studies essentially used candidate gene approaches in very different populations, this does not refute our findings.…”

Diet‐induced DNA methylation within the hypothalamic arcuate nucleus and dysregulated leptin and insulin signaling in the pathophysiology of obesity

“…The importance of POMC methylation status in obesity pathology cannot be overstated, with this locus being identified along with several other candidate genes in linking maternal nutrient exposure to adverse health in human intergenerational studies (James et al, ). All sequenced mammalian POMC genes consist of three exons, separated by two large introns (Millington, ).…”