Placental DNA methylation of peroxisome-proliferator-activated receptor-γ co-activator-1α promoter is associated with maternal gestational glucose level

Abstract

Intrauterine exposure to hyperglycaemia may increase the risk of later-life metabolic disorders. Although the underlying mechanism is not fully understood, epigenetic dysregulation in fetal programming has been implicated. With regard to energy homoeostasis, PGC-1α (peroxisome-proliferator-activated receptor γ co-activator-1α, encoded by the PPARGC1A gene) plays a regulatory role in several biochemical processes. We hypothesized that maternal gestational glucose levels would positively correlate with DNA methylation of the PPARGC1A promoter in placental tissue. We undertook a cross-sectional study of 58 mothers who underwent uncomplicated Caesarean delivery in a university hospital. Maternal gestational glucose concentration was determined after a 75-g OGTT (oral glucose tolerance test) at 24-28 weeks of gestation. Placenta tissue and cord blood were collected immediately after delivery. Genomic DNA was extracted and thereafter bisulfite conversion was performed. After PCR amplification, the DNA methylation of the PPARGC1A promoter was quantified using a pyrosequencing technique. The protein level of PGC-1α was evaluated by Western blotting. For all participants as a whole, including the GDM (gestational diabetes mellitus) and normoglycaemia groups, the maternal gestational glucose level was positively correlated with placental DNA methylation, and negatively correlated with cord blood DNA methylation of the PPARGC1A promoter in a CpG site-specific manner. In the GDM group alone, the placental CpG site-specific methylation of the PPARGC1A promoter strongly correlated with gestational 2-h post-OGTT glycaemia. Epigenetic alteration of the PPAGRC1A promoter may be one of the potential mechanisms underlying the metabolic programming in offspring exposed to intrauterine hyperglycaemia.

Increased Cord Blood Betatrophin Levels in the Offspring of Mothers with Gestational Diabetes

“…A portion of plasma and serum were frozen and stored at -80°C immediately after the centrifugation. Placenta tissue from the fetal side were obtained as previously described [ 31 ]. The samples were rinsed in normal saline at 4°C to remove excess maternal blood.…”

“…Most of the patients in this report were from previously reported cohorts [ 31 ]. All study procedures were approved by the Ethic Committee of Tongji Hospital, Huazhong University of Science and Technology (Approval number: TJ-C20130711), and written informed consent was obtained from each participant in accordance with the Declaration of Helsinki as revised in 2008.…”

MECHANISMS IN ENDOCRINOLOGY: Epigenetic modifications and gestational diabetes: a systematic review of published literature

“…Several studies have studied the methylation pattern of this gene and showed a positive association between fetal DNA methylation and maternal glucose levels (54,56). In addition, adult offspring of GDM mothers had about 40% lower gene expression of PPARGC1A mRNA in skeletal muscle compared to that in controls (77).…”

“…A candidate gene study in placentas of 58 pregnancies with uncomplicated Cesarean delivery (56) showed that maternal glucose levels were positively associated with fetal-placental DNA methylation of PPARGC1A gene. Another study of 85 Chinese women with Cesarean R259 Review G-H Moen and others Epigenetics and gestational diabetes www.eje-online.org delivery, from a different group (57), explored the differences in placental methylation in GDM patients and preeclampsia patients compared to that in controls.…”

“…This association was strengthened after adjustment for circulating levels of adiponectin. The authors concluded that these changes (54,56) ESR1 (59) MEST,NR3C1,ALUs (66) Gene expression:…”