Abstract
Diabetes in pregnancy is associated with increased risk of long-term metabolic disease in the offspring, potentially mediated by in utero epigenetic variation. Previously, we identified multiple differentially methylated single CpG sites in offspring of women with gestational diabetes mellitus (GDM), but whether stretches of differentially methylated regions (DMRs) can also be identified in adolescent GDM offspring is unknown. Here, we investigate which DNA regions in adolescent offspring are differentially methylated in blood by exposure to diabetes in pregnancy. The secondary aim was to characterize the RNA expression of the identified DMR, which contained the nc886 non-coding RNA.
Methods:
To identify DMRs, we employed the bump hunter method in samples from young (9–16 yr, n = 92) offspring of women with GDM (O-GDM) and control offspring (n = 94). Validation by pyrosequencing was performed in an adult offspring cohort (age 28–33 years) consisting of O-GDM (n = 82), offspring exposed to maternal type 1 diabetes (O-T1D, n = 67) and control offspring (O-BP, n = 57). RNA-expression was measured using RT-qPCR in subcutaneous adipose tissue and skeletal muscle.
Results:
One significant DMR represented by 10 CpGs with a bimodal methylation pattern was identified, located in the nc886/VTRNA2-1 non-coding RNA gene. Low methylation status across all CpGs of the nc886 in the young offspring was associated with maternal GDM. While low methylation degree in adult offspring in blood, adipose tissue, and skeletal muscle was not associated with maternal GDM, adipose tissue nc886 expression was increased in O-GDM compared to O-BP, but not in O-T1D. In addition, adipose tissue nc886 expression levels were positively associated with maternal pre-pregnancy BMI (p = 0.006), but not with the offspring’s own adiposity.
Conclusions:
Our results highlight that nc886 is a metastable epiallele, whose methylation in young offspring is negatively correlated with maternal obesity and GDM status. The physiological effect of nc886 may be more important in adipose tissue than in skeletal muscle. Further research should aim to investigate how nc886 regulation in adipose tissue by exposure to GDM may contribute to development of metabolic disease.
Original language | English |
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Article number | 61 |
Journal | Clinical Epigenetics |
Volume | 16 |
Number of pages | 15 |
ISSN | 1868-7075 |
DOIs | |
Publication status | Published - 7 May 2024 |
Bibliographical note
Funding Information:The core analyses of this study were funded by The \u201CFhv. Dir. Leo Nielsen og Hustru Karen Margrethe Nielsens Legat for L\u00E6gevidenskabelig Grundforskning\u201D, Civilingeni\u00F8r Frode V. Nyegaard og Hustru\u2019s Fond, A.P. M\u00F8ller Fonden, and L\u00E6geforeningens Forskningfond. L.H. was funded by The Danish Diabetes Academy supported by the Novo Nordisk Foundation (NNF17SA0031406), and The Danish Diabetes Association (Diabetesforeningen). A.E.S. was funded by the Danish Diabetes Academy, supported by the Novo Nordisk Foundation (NNF17SA0031406). The GDM subcohort clinical study was funded by The Innovation Fund Denmark (09-067124 and 11-115923). LTD is funded by a Novo Nordisk Foundation Challenge Grant (NNF23OC0081177) and a Novo Nordisk Foundation project Grant (NNF22OC0078203). 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).
Keywords
- Adipose
- Developmental programming
- DNA methylation
- Epigenetics
- Gene expression
- Gestational diabetes
- Intrauterine hyperglycemia
- Muscle
- nc886
- ncRNA
- Type 1 diabetes
- VTRNA2-1
Datasets
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Epigenetics of the non-coding RNA nc886 across blood, adipose tissue and skeletal muscle in offspring exposed to diabetes in pregnancy
Hjort, L. (Creator), Bredgaard, S. S. (Creator), Manitta, E. (Creator), Marques, I. (Creator), Sørensen, A. E. (Creator), Martino, D. (Creator), Grunnet, L. G. (Creator), Kelstrup, L. (Creator), Houshmand-Oeregaard, A. (Creator), Clausen, T. D. (Creator), Mathiesen, E. R. (Creator), Olsen, S. F. (Creator), Saffery, R. (Creator), Barrès, R. (Creator), Damm, P. (Creator), Vaag, A. A. (Creator) & Dalgaard, L. T. (Creator), figshare, 8 May 2024
DOI: 10.6084/m9.figshare.c.7221966.v1, https://springernature.figshare.com/collections/Epigenetics_of_the_non-coding_RNA_nc886_across_blood_adipose_tissue_and_skeletal_muscle_in_offspring_exposed_to_diabetes_in_pregnancy/7221966/1
Dataset