Background: Fetal growth is partly regulated by epigenetic factors, such as DNA methylation. Altered methylation status in placental genes relates to gestational diabetes, preeclampsia and prematurity. However, the epigenetic mechanisms underlying fetal growth restraint in uncomplicated pregnancies remain unknown.
Objective and hypotheses: We aimed at identifying new candidate genes related to fetal growth, by assessing DNA methylation profiling in placenta and cord blood -as well as expression levels of differentially methylated genes- in newborns born appropiate- (AGA) or small-for-gestational-age (SGA).
Method: Placentas and cord blood samples were collected from uncomplicated pregnancies delivering term AGA (birthweight, between −1.1 and 1.1 S.D.; n=30) or SGA (birthweight, <−2 S.D.; n=21) newborns. Placental methylation profiling was performed using Agilent DNA Methylation array design to detect CpG sites located within promoter regions of 14.475 genes. Results were validated by bisulfite pyrosequencing (BSP). Differentially methylated genes (n=39, all P<0.009) were also analyzed in cord blood by BSP. Placental and cord blood expression of four out of such 39 genes was assessed by real-time PCR. Body composition was assessed by absorptiometry at age 15 days.
Results: SLC13A5, NKX6-1 and ATG2B -related to hepatic steatosis, insulin production and autophagy were hypermethylated in placenta and cord blood from SGA newborns (P=0.02 to P<0.0001 vs AGA), whereas GPR120 related to free fatty acid regulation was hypomethylated in placenta (P=0.0006) and hypermethylated in cord blood (P<0.0001). Expression levels of these genes were opposite to their methylation status. Both methylation and expression levels in placenta and in cord blood correlated with birthweight and with total and abdominal fat at age 15 days.
Conclusion: Epigenetic modifications of genes involved in the regulation of energy metabolism in placenta and in cord blood contribute to explain fetal growth restraint and postnatal fat mass gain in SGA newborns from uncomplicated pregnancies.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology