The role of DNA methyltransferases in fetal programming

Abstract

Human epidemiological and experimental animal studies show that a poor intra-uterine environment induced by restricted maternal diet during pregnancy leads to persistent alterations in the metabolism and physiology of the offspring and an altered susceptibility to chronic disease in adult life such as cardiovascular disease and metabolic syndrome. This phenomenon has been termed fetal programming. In rats, maternal protein restriction (MPR) during pregnancy alters the expression of specific genes involved in lipid and carbohydrate homeostasis such as glucocorticoid receptor (GR) and peroxisomal proliferator-activated receptor–alpha (PPAR?). Evidence is accumulating which indicates that persistent changes in the expression of GR and PPAR? are mediated by changes in the epigenetic regulation of these genes within the offspring. Epigenetics refers to processes that stably alter gene activity without altering DNA sequence. DNA methylation and histone modification are the most significant epigenetic modifications. However the mechanism by which alterations in maternal diet can induce the altered epigenetic regulation of genes such as GR or PPAR? is currently unknown. The aim therefore of this project was to investigate the role of the DNA methyltransferase1 (Dnmt1). Dnmt1 is essential for the maintenance of DNA methylation patterns in the induction of the altered epigenetic regulation of genes in response to maternal diet. We initially investigated the effect of MPR on Dnmt1 mRNA expression in heart, brain and spleen from control and protein restriction (PR) offspring on PN34. We found that MPR altered the expression of Dnmt1 and the de novo DNA methyltransferases Dnmt3a, and 3b in a tissue specific manner. The effect of MPR on the expression and methylation of GR and PPAR? was also tissue specific. However, in most tissues examined there was not a simple inverse relationship between GR or PPAR? expression and methylation or with levels of Dnmt1 expression. To assess how widespread the changes in gene expression induced by MPR are, microarray analysis was conducted in E8 embryos from control and PR fed dams and results were validated by RT-PCR. Results showed that only relatively small subsets of genes were affected by MPR or global dietary restriction (UN). Gene ontology analysis also revealed that similar pathways were altered under condition of both maternal PR and UN and interestingly one of the pathways altered by both maternal PR and UN was chromatin modification. In both PR and UN embryos on E8 a decrease in Dnmt1, Dnmt3a and 3b expression was observed as well as a decrease in the histone methyltransferases EZH2, Suv39H1 and the HDAC Sirt1 in the embryos from PR dams compared to controls. Alterations in the expression of the DNA and histone methyltransferases in response to MPR were accompanied by changes in DNA methylation and histone modification at the GR promoter as early as E14.

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ORCID for Karen Lillycrop: orcid.org/0000-0001-7350-5489

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