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: These correlations suggest a regulatory relationship between DNA methylation and cardiac‐important genes. Notably, Has2 is essential for endocardial to mesenchymal transformation and heart valve formation.51,55–56,6 Gene network analysis using the Genemania open freeware (http://www.genemania.org) further revealed potential genetic and/or physical interactions among genes or pathways involved in heart development. The top 20 genes that were identified to interact (either genetically or physically) with Has2 by the network analysis were significantly enriched with functions involved in heart development. These genes included Cdh2, Epo, Kcna5, Myocd, Tbx20, Hand1, Mef2c, and Nfatc4 (Figure 6).49,57–59 Regulation of these genes by DNA methylation to influence their expression will ultimately affect their pathway and downstream functions, which are essential for heart development.
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.).