Gestational Diabetes Induced Differential Methylation At Differentially Methylated Region Of Cord Blood MEST And DLK1

Background:Gestational diabetes mellitus(GDM),defined as any degree of glucose intolerance with onset or first recognition during pregnancy,affects 1.7～11.6%of pregnancies.Gestational diabetes mellitus(GDM)is a condition of impaired glucose tolerance first found during pregnancy,and its incidence is increasing all over the world.GDM is one of the main reasons for the increase of maternal and fetal morbidity and mortality.GDM can not only lead to increased incidence of amniotic fluid,shoulder dystocia,premature delivery and neonatal hypoglycemia,but also the long-term risk of chronic diseases such as hypertension,diabetes and obesity.Most of the mechanisms are still unknown,and epigenetic changes may be one of the mechanisms among them.DNA methylation and histone modifications are two major epigenetic mechanisms.DNA methylation has been widely related to imprinting,mammalian development and genomic stability maintenance.MEST(mesoderm specific transcript)is a mesoderm specific transcription factor,also known as the paternal expression gene 1(PEG1),which is located in chromosome 7q32.2,and the encoded protein belongs to the alpha/beta hydrolase folding family.It has been found that hypomethylation of imprinted gene MEST in umbilical cord blood and placental tissue of pregnant women with GDM is closely related to obesity.DLK1(delta-like 1 homologue)is a paternal expression gene,located on chromosome 14q32,encoding a transmembrane protein called preadipocyte factor 1(Pref-1),which inhibits the differentiation of adipocytes.The level of Pref-1 is increased in the fetal blood of small for gestational age(SGA).Pref-1 is considered to be the determining factor of adipocyte differentiation and obesity.Therefore,Pref-1 is associated with the high risk of metabolic diseases in adulthood.Aims:The aims of the current investigation were to determine the neonatal umbilical cord blood’s methylation levels at differentially methylated regions(DMRs)of MEST and DLK1 of GDM women and to explore the possible mechanisms underlying the association between GDM and risk for chronic diseases in adulthood.Material and Methods:Lymphocytes were isolated from umbilical cord blood of infants born to 95 women with GDM and 93 women with normal pregnancy.DNA methylation levels of MEST and DLK1 DMRs were determined by MassARRAY quantitative methylation analysis.Results:The methylation levels were detected in 16 CpG sites and aggregates of multiple CpG sites of MEST DMRs and 12 sites of DLK1 DMRs.Methylation levels were lower at CpG 1(p=0.016),and higher at CpG 7.8,CpG 21 of MEST DMR in GDM compared to normal pregnancy(p=0.011,0.029),but there were no significant differences in methylation levels at other detected sites(p>0.05 for all).There were no significant differences in methylation levels at any detected CpG sites of DLK1 DMR between GDM and normal pregnancy(p>0.05 for all).Conclusion:We concluded GDM induced a different methylation at MEST DMR,and this might be among the mechanisms underlying the association between intrauterine exposure to GDM and risk for chronic diseases in adulthood.