The Role of DNA Methylation in Heart Development and Disease

Abstract

Heart malformations and anomalies affect 3-5% of the population, with 1% of the population presenting with a congenital heart defect (CHD). Offspring developing in an abnormal environment, such as maternal hyperglycemia, have an increased risk of developing a CHD. Identifying the molecular and cellular mechanisms underlying such defects is necessary for developing new diagnostic and therapeutic strategies to improve the prognosis of patients.;In this thesis I address the hypothesis that DNA methylation and DNA methyltransferase 3b (Dnmt3b) play important roles in heart development and disease, as the role for DNA methylation in the developing heart has not been defined, although loss of Dnmt3b has been linked to CHD.;To test this hypothesis, I generated a genome-wide profile of DNA methylation in developing mouse hearts and showed that global levels of DNA methylation remain stable during mid-stage cardiac development, but changes occur at a subset of loci including a significant number of genes involved in cardiac development and function. Further analysis identified potential functional relationships between DNA methylation and gene expression for a number of cardiac important genes, including hyaluronan synthase 2 (Has2). I then showed that Dnmt3b is required for suppressing Has2 expression within endocardial cells and their mesenchymal progeny, and that loss of Dnmt3b within the endocardium results in developmental delay and heart valve defects. These results suggest abnormal DNA methylation in the developing heart is likely involved in development of CHD.;To further understand how changes in the maternal environment affect DNA methylation and heart formation, DNA methylation profiles of mouse hearts collected from pups born to hyperglycemic and euglycemic mothers were examined and results showed that maternal hyperglycemia contributes to dysregulation of DNA methylation in the hearts of offspring that may contribute to the increased frequency of CHDs.;All together, the findings of this thesis work enhance the knowledge base of regulation of heart development and disease by DNA methylation and provides a new avenue to pursue regarding diagnostic and therapeutic strategies.