Abstract
BackgroundInsulin-like growth factors 1 and 2 (IGF1 and IGF2) and their binding proteins (IGFBPs) are expressed in the placenta and known to regulate fetal growth. DNA methylation is an epigenetic mechanism which involves addition of methyl group to a cytosine base in the DNA forming a methylated cytosine-phosphate-guanine (CpG) dinucleotide which is known to silence gene expression. This silences gene expression, potentially altering the expression of IGFs and their binding proteins. This study investigates the relationship between DNA methylation of components of the IGF axis in the placenta and disorders in fetal growth. Placental samples were obtained from cord insertions immediately after delivery from appropriate, small (defined as birthweight <10th percentile for the gestation [SGA]) and macrosomic (defined as birthweight > the 90th percentile for the gestation [LGA]) neonates. Placental DNA methylation, mRNA expression and protein levels of components of the IGF axis were determined by pyrosequencing, rtPCR and Western blotting.ResultsIn the placenta from small for gestational age (SGA) neonates (n = 16), mRNA and protein levels of IGF1 were lower and of IGFBPs (1, 2, 3, 4 and 7) were higher (p < 0.05) compared to appropriately grown neonates (n = 37). In contrast, in the placenta from large for gestational age (LGA) neonates (n = 20), mRNA and protein levels of IGF1 was not different and those of IGFBPs (1, 2, 3 and 4) were lower (p < 0.05) compared to appropriately grown neonates. Compared to appropriately grown neonates, CpG methylation of the promoter regions of IGF1 was higher in SGA neonates. The CpG methylation of the promoter regions of IGFBP1, IGFBP2, IGFBP3, IGFBP4 and IGFBP7 was lower in the placenta from SGA neonates as compared to appropriately grown neonates, but was unchanged in the placenta from LGA neonates.ConclusionsOur results suggest that changes in CpG methylation contribute to the changes in gene expression of components of the IGF axis in fetal growth disorders. Differential methylation of the IGF1 gene and its binding proteins is likely to play a role in the pathogenesis of SGA neonates.
Highlights
Insulin-like growth factors 1 and 2 (IGF1 and insulin-like growth factor 2 (IGF2)) and their binding proteins (IGFBPs) are expressed in the placenta and known to regulate fetal growth
Placental messenger ribonucleic acid (mRNA) expression and protein expression of the IGF axis and its binding proteins Compared to appropriately grown neonates, the placental mRNA expression of insulin-like growth factor 1 (IGF1) was reduced in the small for gestational age (SGA) group but not in the large for gestational age (LGA) group (Fig. 1)
Our study has demonstrated that in pregnancies affected by SGA, the placental IGF and IGFBP axis is altered; we found that placental IGF1 mRNA is decreased, the IGFBPs expression is increased and these changes are associated with alterations in DNA methylation levels of IGF1 and IGFBPs
Summary
Insulin-like growth factors 1 and 2 (IGF1 and IGF2) and their binding proteins (IGFBPs) are expressed in the placenta and known to regulate fetal growth. DNA methylation is an epigenetic mechanism which involves addition of methyl group to a cytosine base in the DNA forming a methylated cytosine-phosphate-guanine (CpG) dinucleotide which is known to silence gene expression This silences gene expression, potentially altering the expression of IGFs and their binding proteins. Insulin-like growth factors 1 and 2 (IGF1, IGF2) are expressed in the placenta and are known to regulate fetal growth [1]. IGFBP3 is the most common binding protein found in the placenta [23], IGF1 and IGFBP1 appear to play the major role in regulating fetal growth. The increased activity of proteases during pregnancy shifts the control of IGF action from IGFBP3 to IGFBP1
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