Gestational diabetes mellitus placentas exhibit epimutations at placental development genes

ABSTRACT

Gestational diabetes mellitus (GDM) is a maternal metabolic disorder that perturbs placental development and increases the risk of offspring short- and long-term metabolic disorders. The mechanisms by which GDM impairs placental development remain poorly understood. Here, we defined the DNA methylome of GDM placentas and determined whether GDM perturbs methylation at genes important for placental development. We conducted an epigenome-wide association study of 42 placentas from pregnancies in the South African Soweto First 1000 days cohort (S1000). Using genome-wide bisulfite sequencing, we compared non-GDM placentas to GDM placentas with similar proportions from obese and non-obese mothers. Compared to non-GDM, GDM placentas exhibited a distinct methylation profile consisting of 12,210 differentially methylated CpGs (DMCs) that mapped to 3,875 genes. Epigenetically altered genes were enriched in Wnt and cadherin signalling pathways, both critical in placentation and embryogenesis. We also defined regional DNA methylation perturbation in GDM placentas at 11 placental development genes. These findings reveal extensive changes to the placental epigenome of GDM pregnancies and highlight perturbation enriched at important placental development genes. These molecular changes represent potential mechanisms for GDM-induced placental effects that may serve as candidate biomarkers for placental, maternal, and foetal health. Using a study design that used similar proportions of obese and non-obese mothers in our case and control pregnancies, we minimized the detection of changes due to obesity alone. Further work will be necessary to investigate the extent of the influence of obesity on these GDM-related placental epigenetic changes.

KEYWORDS:

• Epigenetics
• placenta
• development
• developmental programming
• gestational diabetes mellitus
• DNA methylation

Acknowledgments

We thank the Soweto First 1000 Days Study participants; Yusuf Guman and the MRC/Wits Developmental Pathways for Health Research Unit research staff for acquiring the placental samples and data; the Genomics Laboratory at the David H. Murdock Research Institute (DHMRI) for sequencing data; Edward Pietryk, Talia Kieu and Gabriella Gentile for technical assistance.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

We declare that this study was conceptualized by FI, LA, and SN, with input on study design from LM, RG, CB, & CJ. Cohort recruitment and management, sample collection, and selection supervised by SN. Sample preparation was performed by FI, JX, & LM. Data analyses were performed by LM & RG under the supervision of FI, CB, & CJ with input from JX. The manuscript was drafted and revised by LM & FI with input from all authors. All authors have seen and approved the final version of the manuscript.

Ethics approval and consent to participate

The work reported here was conducted following The Code of Ethics of the World Medical Association, approved by the Human Research Ethics Committee (Medical) at the University of the Witwatersrand, and reviewed and cleared by the Office of Human Research Ethics at the University of North Carolina at Chapel Hill. Informed consent was obtained from all individual participants included in the study.

Data availability statement

The datasets used during the study are currently available from the corresponding authors on reasonable requests. Data will be available within 6 months of the paper acceptance date at GEO through NCBI.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15592294.2022.2111751

Additional information

Funding

NIEHS [KES023849A], UNC Nutrition Research Institute Pilot Grant, UNC CEHS Pilot Grant [5P30ES010126], NIDDK [R21DK122242] to FI; UK Medical Research Council (MRC) DFID African Research Leader Scheme Award to SN; NHLBI T32 – Global Cardiometabolic Disease Training Grant [5T32HL129969], P.E.O Scholar Award, and UNC Dissertation Completion Fellowship to LM. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.