IGF2 DNA methylation is a modulator of newborn’s fetal growth and development

Placental 5-methylcytosine and 5-hydroxymethylcytosine patterns associate with size at birth

“…31 Although the techniques used in our study do not permit us to compare the relative enrichment of 5mC and 5hmC quantitatively, the presence of 5hmC within DMRs in imprinted regions in human placenta mean that studies of DNA methylation using conventional bisulfite conversion might overestimate 5mC levels at DMRs, particularly if the results of such studies are used to infer potential effects of altered methylation on gene expression. Our findings of significant enrichment of 5hmC and a lower enrichment of 5mC at DMR2 relative to the other DMRs analyzed suggest that studies using bisulfite conversion techniques that report small changes in cytosine methylation at DMRs, including at this region, 18 could overestimate the amount of 5mC present. Additionally, the presence of (and/or changes in) 5hmC at the same loci could complicate any interpretation of downstream effects on gene expression, since the role of 5hmC at imprinted DMRs is unclear.…”

“…13 Approximately 50% of growthrestricted individuals with SRS cases show loss of methylation at ICR1, which could lead to decreased IGF2 expression and consequent growth restriction. 8,14 IGF2 expression is additionally modulated by DNA methylation at a number of other DMRs, 15 and altered placental and umbilical cord 5mC at DMRs controlling IGF2 expression has been reported in association with fetal growth restriction in some, [16][17][18][19] but not all 15,20 studies.…”

Placental expression profile of imprinted genes impacts birth weight

“…The 9 imprinted genes we identified driving these phenotypes showed levels of expression that were, for the most part, positively associated with LGA status and include several genes previously implicated with birth weight. Genetic variants in H19, 13 methylation levels at differentially methylated regions (DMRs) of MEG3, 14 PLAGL1, [14][15][16] and IGF2/H19, 15,17 and protein levels of IGF2 18 have been observed to be relevant to birth weight, although the direction of the association with birth weight across these studies is not always consistent. For example, while paternally expressed IGF2 serum levels and mRNA expression levels have been positively associated with infant birth weight, 17,18 both positive and negative associations have been reported linking IGF2-DMR methylation with birth weight.…”

“…Genetic variants in H19, 13 methylation levels at differentially methylated regions (DMRs) of MEG3, 14 PLAGL1, [14][15][16] and IGF2/H19, 15,17 and protein levels of IGF2 18 have been observed to be relevant to birth weight, although the direction of the association with birth weight across these studies is not always consistent. For example, while paternally expressed IGF2 serum levels and mRNA expression levels have been positively associated with infant birth weight, 17,18 both positive and negative associations have been reported linking IGF2-DMR methylation with birth weight. 15,17,18 Such discrepancies, particularly relating DMR methylation and expression, is not uncommon in the literature and points to the importance of further clarifying the regulatory process of these genes.…”

“…For example, while paternally expressed IGF2 serum levels and mRNA expression levels have been positively associated with infant birth weight, 17,18 both positive and negative associations have been reported linking IGF2-DMR methylation with birth weight. 15,17,18 Such discrepancies, particularly relating DMR methylation and expression, is not uncommon in the literature and points to the importance of further clarifying the regulatory process of these genes. In addition to validating the existing literature, we also identified novel loci associated with birth weight, including the expression levels of BLCAP, MEST, NNAT, and NDN.…”