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Epigenetic and transcriptomic alterations in offspring born to women with type 1 diabetes (the EPICOM study)
Sine Knorr1,2,3, Anne Skakkebæk4,5, Jesper Just4
1Steno Diabetes Center Aarhus, Aarhus University Hospital, Hedeager 3, 2. fl, 8200, Aarhus, DK, Denmark. sine.knorr@clin.au.dk.
Insights
Maternal type 1 diabetes (T1DM) in pregnancy may alter offspring DNA methylation and gene expression. These epigenetic changes in offspring could increase the risk of future metabolic and vascular diseases.
Area of Science:
- Epigenetics
- Developmental Biology
- Metabolic Disease
Background:
- Offspring of mothers with pregestational type 1 diabetes (T1DM) face intrauterine hyperglycemic conditions.
- This exposure is linked to an elevated risk of developing metabolic diseases later in life.
Purpose of the Study:
- To investigate if in utero exposure to T1DM alters offspring DNA methylation and gene expression.
- To determine if these alterations impact the offspring's risk of future disease.
Main Methods:
- Utilized data from the Epigenetic, Genetic and Environmental Effects on Growth, Metabolism and Cognitive Functions in Offspring of Women with Type 1 Diabetes (EPICOM) study.
- Analyzed DNA methylation (450K-Illumina Infinium assay) and RNA expression (RNA sequencing) in leukocytes from adolescent offspring (n=20) of mothers with T1DM and matched controls (n=20).
Main Results:
- Identified significant differences in gene co-expression networks associated with maternal T1DM exposure.
- Functional enrichment analysis revealed links to diabetes, carbohydrate/glucose metabolism, MAPK signaling, and conditions like obesity and atherosclerosis.
- Six genes showed corresponding methylation and RNA expression changes (CIITA, TPM1, PXN, ST8SIA1, LIPA, DAXX).
Conclusions:
- Intrauterine exposure to maternal T1DM may induce lasting epigenetic modifications (methylation and gene expression) in offspring.
- These epigenetic profiles may contribute to the increased susceptibility to vascular and metabolic diseases observed in offspring of mothers with T1DM.
Background:
Offspring born to women with pregestational type 1 diabetes (T1DM) are exposed to an intrauterine hyperglycemic milieu and has an increased risk of metabolic disease later in life. In this present study, we hypothesize that in utero exposure to T1DM alters offspring DNA methylation and gene expression, thereby altering their risk of future disease.
Methods:
Follow-up study using data from the Epigenetic, Genetic and Environmental Effects on Growth, Metabolism and Cognitive Functions in Offspring of Women with Type 1 Diabetes (EPICOM) collected between 2012 and 2013.
Setting:
Exploratory sub-study using data from the nationwide EPICOM study.
Participants:
Adolescent offspring born to women with T1DM (n=20) and controls (n=20) matched on age, sex, and postal code.
Main Outcome Measures:
This study investigates DNA methylation using the 450K-Illumina Infinium assay and RNA expression (RNA sequencing) of leucocytes from peripheral blood samples.
Results:
We identified 9 hypomethylated and 5 hypermethylated positions (p < 0.005, |ΔM-value| > 1) and 38 up- and 1 downregulated genes (p < 0.005, log2FC ≥ 0.3) in adolescent offspring born to women with T1DM compared to controls. None of these findings remained significant after correction for multiple testing. However, we identified differences in gene co-expression networks, which could be of biological significance, using weighted gene correlation network analysis. Interestingly, one of these modules was significantly associated with offspring born to women with T1DM. Functional enrichment analysis, using the identified changes in methylation and gene expression as input, revealed enrichment in disease ontologies related to diabetes, carbohydrate and glucose metabolism, pathways including MAPK1/MAPK3 and MAPK family signaling, and genes related to T1DM, obesity, atherosclerosis, and vascular pathologies. Lastly, by integrating the DNA methylation and RNA expression data, we identified six genes where relevant methylation changes corresponded with RNA expression (CIITA, TPM1, PXN, ST8SIA1, LIPA, DAXX).
Conclusions:
These findings suggest the possibility for intrauterine exposure to maternal T1DM to impact later in life methylation and gene expression in the offspring, a profile that may be linked to the increased risk of vascular and metabolic disease later in life.
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