DNA methylation is developmentally regulated for genes essential for cardiogenesis.
Bottom Line: Quantitative real-time PCR analysis of 350 genes with differential DNA methylation showed that the expression of 181 genes is developmentally regulated, and 79 genes have correlative changes between methylation and expression, including hyaluronan synthase 2 (Has2).Required for heart valve formation, Has2 expression in the developing heart valves is downregulated at E14.5, accompanied with increased DNA methylation in its enhancer.Genetic knockout further showed that the downregulation of Has2 expression is dependent on DNA methyltransferase 3b, which is co-expressed with Has2 in the forming heart valve region, indicating that the DNA methylation change may contribute to the Has2 enhancer's regulating function.
Affiliation: Division of Hematology, Department of Genetics, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY (A.A.C., M.L., A.A.M., Y.W., M.S., B.W., J.M.G., D.Z.).Show MeSH
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Mentions: To investigate the functional importance of the small set of genes exhibiting differential methylation, we used the software GREAT to characterize the 2901 differentially methylated sites for their potential regulatory roles. Of the only 7 significantly associated gene ontology (GO) terms for biological processes returned by GREAT, 4 of them were related to heart development and cardiac tissue growth (Figure 4), indicating a significant enrichment of cardiac essential genes that have differential DNA methylation during heart development. These genes include Erbb4, Gata6, Foxp1, Fgf2, Fgf9, Has2, Invs, Mef2c, Robo2, and Wnt2. For example, Foxp1 is important in cardiomyocyte proliferation,42,46 while signaling from Gata6 to Wnt2 plays an important role in early cardiogenesis and inflow tract development,47–48Mef2c plays an essential role in heart development as a regulator of cardiac myogenesis within the right ventricle,49–50 and Has2 plays a role in heart valve development.6,51 GREAT also reported that the affected genes were highly expressed in the cardiovascular system (P=5.3e‐5) and they were implicated in vascular disease (P=1.4e‐4) based on an analysis of Disease Ontology.52
Affiliation: Division of Hematology, Department of Genetics, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY (A.A.C., M.L., A.A.M., Y.W., M.S., B.W., J.M.G., D.Z.).