Placental DNA methylation in pregnancies complicated by maternal diabetes and/or obesity: State of the art and research gaps

Abstract

Maternal diabetes and/or obesity in pregnancy are undoubtedly associated with later disease-risk in the offspring. The placenta, interposed between the mother and the foetus, is a potential mediator of this risk through epigenetic mechanisms, including DNA methylation. In recent years, multiple studies have identified differentially methylated CpG sites in the placental tissue DNA in pregnancies complicated by diabetes and obesity. We reviewed all published original research relevant to this topic and analysed our findings with the focus of identifying overlaps, contradictions, and gaps. Most studies focused on the association of gestational diabetes and/or hyperglycaemia in pregnancy and DNA methylation in placental tissue at term. We identified overlaps in results related to specific candidate genes, but also observed a large research gap of pregnancies affected by type 1 diabetes. Other unanswered questions relate to analysis of specific placental cell types and the timing of DNA methylation change in response to diabetes and obesity during pregnancy. Maternal metabolism is altered already in the first trimester involving structural and functional changes in the placenta, but studies into its effects on placental DNA methylation during this period are lacking and urgently needed. Foetal sex is also an important determinant of pregnancy outcome, but only few studies have taken this into account. Collectively, we provide a reference work for researchers working in this large and evolving field. Based on the results of the literature review, we formulate suggestions for future focus of placental DNA methylation studies in pregnancies complicated by diabetes and obesity.

Keywords: DNA methylation; Pregnancy; epigenetic; foetal development; gestational diabetes; hyperglycaemia; hyperlipidaemia; obesity; offspring; placenta; type 1 diabetes; type 2 diabetes.

Figure 1.

Overview of literature search strategy and screening of included and excluded original research papers.

Figure 2.

Percental overviews of number of studies conducted stratifying: A. by disease or trait, B. by placental tissue type, and C. by methodology. Abbreviations: GDM: Gestational Diabetes Mellitus, T1DM: Type 1 Diabetes Mellitus, T2DM: Type 2 Diabetes Mellitus, RRBS: reduced representation bisulphite sequencing, LC-MS/MS: liquid chromatography with tandem mass spectrometry, LUMA: Luminometric Methylation Assay, EWAS: epigenome wide association study, MEDIP: methylated DNA immunoprecipitation, BS, bisulphite sequencing, MS-PCR: methylation-specific PCR, PS: pyrosequencing.