Abstract
BackgroundIntrauterine growth restriction (IUGR), which refers to reduced fetal growth in the context of placental insufficiency, is etiologically heterogeneous. IUGR is associated not only with perinatal morbidity and mortality but also with adult-onset disorders, such as cardiovascular disease and diabetes, posing a major health burden. Placental epigenetic dysregulation has been proposed as one mechanism that causes IUGR; however, the spectrum of epigenetic pathophysiological mechanisms leading to IUGR remains to be elucidated. Monozygotic monochorionic twins are particularly affected by IUGR, in the setting of severe discordant growth. Because monozygotic twins have the same genotype at conception and a shared maternal environment, they provide an ideal model system for studying epigenetic dysregulation of the placenta.ResultsWe compared genome-wide placental DNA methylation patterns of severely growth-discordant twins to identify novel candidate genes for IUGR. Snap-frozen placental samples for eight severely growth-discordant monozygotic monochorionic twin pairs were obtained at delivery from each twin. A high-resolution DNA methylation array platform was used to identify methylation differences between IUGR and normal twins. Our analysis revealed differentially methylated regions in the promoters of eight genes: DECR1, ZNF300, DNAJA4, CCL28, LEPR, HSPA1A/L, GSTO1, and GNE. The largest methylation differences between the two groups were in the promoters of DECR1 and ZNF300. The significance of these group differences was independently validated by bisulfite pyrosequencing, implicating aberrations in fatty acid beta oxidation and transcriptional regulation, respectively. Further analysis of the array data identified methylation changes most prominently affecting the Wnt and cadherin pathways in the IUGR cohort.ConclusionsOur results suggest that IUGR in monozygotic twins is associated with impairments in lipid metabolism and transcriptional regulation as well as cadherin and Wnt signaling. We show that monozygotic monochorionic twins discordant for growth provide a useful model to study one type of the epigenetic placental dysregulation that drives IUGR.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0238-x) contains supplementary material, which is available to authorized users.
Highlights
Intrauterine growth restriction (IUGR), which refers to reduced fetal growth in the context of placental insufficiency, is etiologically heterogeneous
After accounting for the potential confounding effects of the twins’ sex, gestational age, and maternal age, our analysis revealed eight statistically significant (p < 0.05) differentially methylated region (DMR) where the magnitude of the DNA methylation (DNAm) differences between IUGR and the other twin exceeded 10 % (Table 1)
To the best of our knowledge, this is the first report that prominently highlights these pathways in the pathogenesis of IUGR in growth-discordant MC twins. This is the first report of a genome-wide DNA methylation analysis using the Infinium HumanMethylation450 BeadChip platform to investigate IUGR in MC growthdiscordant twins
Summary
Intrauterine growth restriction (IUGR), which refers to reduced fetal growth in the context of placental insufficiency, is etiologically heterogeneous. IUGR is associated with perinatal morbidity and mortality and with adult-onset disorders, such as cardiovascular disease and diabetes, posing a major health burden. When growth restriction occurs in the context of placental insufficiency, it is termed intrauterine growth restriction (IUGR). IUGR, which affects 10–15 % of pregnancies [2], is associated with significant perinatal morbidity and mortality [2] and with adult-onset diseases, such as cardiovascular disease and diabetes [3,4,5]. The association between IUGR and adult-onset disease is thought to result from fetal programming, wherein fetal adaptive mechanisms “set” metabolic regulatory pathways in response to fetal environments, such as limited nutrition. The molecular basis of fetal programming is likely to be mediated by epigenetic mechanisms such as DNA methylation
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