Epigenetic alteration of Rho guanine nucleotide exchange Factor 11 (ARHGEF11) in cord blood samples in macrosomia exposed to intrauterine hyperglycemia

Abstract

Background: Macrosomia at birth is associated with maternal hyperglycemia and leads to subsequent susceptibility to obesity, abnormal glucose metabolism, hypertension, and dyslipidemia in offspring. Epigenetic reprogramming has been reported to be involved in the development of human diseases caused by suboptimal environmental or nutritional factors. The study was aiming to explore epigenetic mechanism influences on macrosomic infants exposed to intrauterine hyperglycemia. We performed a genome-wide analysis of DNA methylation in cord blood from macrosomic infants born to women with gestational diabetes in order to identify genes related to fetal growth or early adipose tissue development.

Methods: To analyze the epigenetic patterns in umbilical cord blood in gestational diabetes mellitus (GDM), we collected umbilical cord blood from women with GDM (mean pregestational BMI of 24.4 kg/m² and mean neonatal birth weight of 4366 g) and normal glucose-tolerant women (mean pregestational BMI of 19.8 kg/m² and mean neonatal birth weight of 3166 g). Differentially methylated genes in the GDM group were identified using the Infinium HumanMethylation450 BeadChip array.

Results: A total of 1251 genes were differentially methylated compared to the controls (p < .01). The methylation microarray data showed that two specific CpG sites (cg12604331 and cg08480098) in the gene body of ARHGEF11 were significantly hypomethylated in the cord blood in macrosomic infants. Altered DNA methylation levels of ARHGEF11 were negatively correlated with glucose levels and neonatal birth weight.

Conclusions: Exposure to adverse intrauterine environments can alter fetal development, such as by affecting the nutritional status of the fetus. Such exposure can also result in significant epigenetic modifications, including DNA methylation, which could serve as a potential marker for nutrition and metabolic conditions at the neonatal stage or even in the adult.

Keywords:

• DNA methylation
• epigenetics
• gestational diabetes mellitus
• macrosomia
• obesity
• Rho guanine nucleotide exchange Factor 11

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [Grant nos. 81401215 and 81830044], the Natural Science Foundation of Beijing Municipality [Grant no. 7192206], Beijing Talents Foundation from organization department of Beijing municipal committee of the CPC [Grant no. 2016000021223ZK20], and Peking University Medicine Fund of Fostering Young Scholars’ Scientific & Technological Innovation [Grant no. BMU2018PY002].