DNA Methylation and Gene Expression in Blood and Adipose Tissue of Adult Offspring of Women with Diabetes in Pregnancy-A Validation Study of DNA Methylation Changes Identified in Adolescent Offspring

Eleonora Manitta; Irene Carolina Fontes Marques; Sandra Stokholm Bredgaard; Louise Kelstrup; Azadeh Houshmand-Oeregaard; Tine Dalsgaard Clausen; Louise Groth Grunnet; Elisabeth Reinhardt Mathiesen; Louise Torp Dalgaard; Romain Barrès; Allan Arthur Vaag; Peter Damm; Line Hjort

doi:10.3390/biomedicines10061244

DNA Methylation and Gene Expression in Blood and Adipose Tissue of Adult Offspring of Women with Diabetes in Pregnancy-A Validation Study of DNA Methylation Changes Identified in Adolescent Offspring

Biomedicines. 2022 May 26;10(6):1244. doi: 10.3390/biomedicines10061244.

Authors

Eleonora Manitta¹, Irene Carolina Fontes Marques², Sandra Stokholm Bredgaard³, Louise Kelstrup^{2

4

5}, Azadeh Houshmand-Oeregaard^{2

6}, Tine Dalsgaard Clausen^{4

7}, Louise Groth Grunnet⁸, Elisabeth Reinhardt Mathiesen^{4

9}, Louise Torp Dalgaard³, Romain Barrès¹, Allan Arthur Vaag⁸, Peter Damm^{2

4}, Line Hjort^{1

2}

Affiliations

¹ Novo Nordisk Foundation Center for Basic Metabolic Research, Metabolic Epigenetics Group, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
² Department of Obstetrics, Center for Pregnant Women with Diabetes, Rigshospitalet, 2100 Copenhagen, Denmark.
³ Department of Science and Environment, Roskilde University, 4000 Roskilde, Denmark.
⁴ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
⁵ Department of Obstetrics and Gynecology, Herlev and Gentofte Hospital, 2730 Herlev, Denmark.
⁶ Novo Nordisk A/S, Novo Allé 1, 2880 Bagsværd, Denmark.
⁷ Department of Obstetrics and Gynecology, Hillerød Hospital, 3400 Hillerød, Denmark.
⁸ Steno Diabetes Center Copenhagen, Herlev Hospital, 2730 Herlev, Denmark.
⁹ Department of Endocrinology, Rigshospitalet, 2100 Copenhagen, Denmark.

Abstract

Maternal gestational diabetes and obesity are associated with adverse outcomes in offspring, including increased risk of diabetes and cardiovascular diseases. Previously, we identified a lower DNA methylation degree at genomic sites near the genes ESM1, MS4A3, and TSPAN14 in the blood cells of adolescent offspring exposed to gestational diabetes and/or maternal obesity in utero. In the present study, we aimed to investigate if altered methylation and expression of these genes were detectable in blood, as well in the metabolically relevant subcutaneous adipose tissue, in a separate cohort of adult offspring exposed to gestational diabetes and obesity (O-GDM) or type 1 diabetes (O-T1D) in utero, compared with the offspring of women from the background population (O-BP). We did not replicate the findings of lower methylation of ESM1, MS4A3, and TSPAN14 in blood from adults, either in O-GDM or O-T1D. In contrast, in adipose tissue of O-T1D, we found higher MS4A3 DNA methylation, which will require further validation. The adipose tissue ESM1 expression was lower in O-GDM compared to O-BP, which in turn was not associated with maternal pre-pregnancy BMI nor the offspring's own adiposity. Adipose tissue TSPAN14 expression was slightly lower in O-GDM compared with O-BP, but also positively associated with maternal pre-pregnancy BMI, as well as offspring's own adiposity and HbA1c levels. In conclusion, the lower DNA methylation in blood from adolescent offspring exposed to GDM could not be confirmed in the present cohort of adult offspring, potentially due to methylation remodeling with increased aging. In offspring adipose tissue, ESM1 expression was associated with maternal GDM, and TSPAN14 expression was associated with both maternal GDM, as well as pre-pregnancy BMI. These altered expression patterns are potentially relevant to the concept of developmental programming of cardiometabolic diseases and require further studies.

Keywords: DNA methylation; ESM1; MS4A3; TSPAN14; adipose tissue; developmental programming; epigenetics; gene expression; gestational diabetes; intrauterine hyperglycemia; type 1 diabetes.

Grants and funding

The Danish Diabetes Academy supported by the Novo Nordisk Foundation, The Danish Diabetes Association (Diabetesforeningen), Civilingeniør Frode V. Nyegaard og Hustru’s Fond, A.P. Møller Fonden, Lægeforeningens Forskningfond. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research center at the University of Copenhagen, partially funded by an unrestricted donation from the Novo Nordisk Foundation (NNF18CC0034900).