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DNA methylation profiles in sibling pairs discordant for intrauterine exposure to maternal gestational diabetes

ABSTRACT: Intrauterine exposure to hyperglycemic environment is reported to confer increased metabolic risk in later life, supporting the “developmental origins of health and disease” hypothesis. Epigenetic alterations are suggested as one of the possible underlying mechanisms. We measured DNA methylation using Infinium HumanMethylation450 BeadChip in siblings discordant for maternal gestational diabetes mellitus (GDM), which may allow possible genetic and environmental confounding effects to be reduced. Of the 465,447 CpG sites analyzed, 12 showed differential methylation (false discovery rate < 0.15), including markers within genes associated with monogenic diabetes (HNF4A) or obesity (RREB1). The overall methylation at the HNF4A gene region showed inverse correlations with mRNA expression levels though non-significant. In a gene set enrichment analysis, differentially methylated CpGs-associated genes were involved in metabolism and signal transduction pathways. Our findings implicate epigenetic mechanisms in relation to prenatal exposure to maternal hyperglycemia.

ORGANISM(S): Homo sapiens

PROVIDER: GSE102177 | GEO | 2017/08/03

SECONDARY ACCESSION(S): PRJNA396908

REPOSITORIES: GEO

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Project description:The prevalence of metabolic syndrome comprising obesity, type 2 diabetes mellitus and cardiovascular disease has been on the rise world-wide in recent years. As non-communicable diseases such as type 2 diabetes mellitus have their roots in prenatal development and conditions such as maternal gestational diabetes (GDM), we aimed to test this hypothesis in primary cells derived from the offspring of GDM mothers compared to control subjects. Methods We have assessed primary umbilical cord derived cells such as human vascular endothelial cells (HUVECs) and Wharton’s jelly derived mesenchymal stem cells (WJMSCs) from both, the offspring of GDM and healthy mothers. We have compared the primary isolates in cell based assays measuring proliferation, mitochondrial oxygen consumption, as well as the ability to support blood vessel growth. We conducted gene expression microarray studies with subsequent pathway analysis and candidate gene validation. Results We observed striking differences between the two groups such as lower metabolic rates and impairment of tube formation in cells with GDM background. HUVECs from subjects with maternal GDM have lower expression of the anti-apoptotic protein BCL-Xl suggesting compromised angiogenic capabilities. Comparative gene expression analysis revealed blood vessel formation as a major pathway enriched in the GDM derived HUVECs with the surface marker CD44 as a significant gene under-expressed in the GDM group. Functional validation of CD44 revealed that it regulates tube formation in HUVECs thereby providing new insights into a novel pathway imprinted in primary umbilical cord derived cells from GDM offspring. Conclusions/interpretation Our data demonstrate that primary cells isolated from the umbilical cord of offspring born to GDM mothers maintain metabolic and molecular imprints of maternal hyperglycemia, which occurred during prenatal development reflecting an enhanced risk for cardiovascular disease later in life.

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DNA methylation profiles in sibling pairs discordant for intrauterine exposure to maternal gestational diabetes

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