Abstract / Summary
Aim: To identify differentially methylated genes in offspring of obese versus lean mothers using a mouse model of maternal obesity. Background: Adverse conditions during fetal development predispose offspring to adult diseases, supporting the theory of fetal programming. DNA methylation is suggested as a mechanism by which maternal obesity induces fetal programming. As maternal obesity predisposes offspring to chronic kidney disease (CKD), we aimed to investigate the role of DNA methylation in maternal obesity related to CKD in the offspring. Methods: Maternal obesity was modelled by feeding female C57BL/6 mice a high-fat diet before breeding, and during gestation and lactation. Control dams received chow. Male offspring were weaned to chow on postnatal day 20 and were sacrificed at 32 weeks of age (adulthood). Another cohort was sacrificed at birth. Reduced representation bisulfite sequencing was used to identify differentially methylated genes (DMGs) in the offspring kidney and blood at adulthood and at birth. Real-time PCR was used to determine gene expression. Results: Adult offspring of obese dams showed significant DMGs in both kidney and blood at adulthood in association with increased levels of kidney injury. Among these, 10 genes were differentially methylated in the kidney, out of which, four genes were also differentially methylated in the blood. An additional 10 genes were differentially methylated in the blood only. Renal mRNA expression of four genes (Rcsd1, Cdk8, Taco1 and Axin2) was significantly upregulated, confirming transcriptional alteration of these genes in the offspring due to epigenetic regulation. Pathway analysis revealed enrichment of genes involved in the Wnt canonical signalling pathway. In comparison, no significant DMGs were detected at day 1. Conclusions: Maternal obesity induced differential gene methylation in the kidneys and blood of adult offspring. Several of these genes have shown high relevance to kidney fibrosis, diabetes or obesity, supporting the role of epigenetic regulation in fetal programming to CKD by maternal obesity.