Abstract 19534: Histone Methylation Regulates the Electrophysiologic Phenotype
Histone methylation regulates development, cellular identity, and stem cell potential. The role of histone methylation in differentiated tissue remains unstudied. Accordingly, we sought to determine whether histone methylation regulates gene expression in adult differentiated myocytes. We utilized a floxed allele of the Pax transactivation-domain interacting protein (PTIP) to generate tamoxifen-inducible cardiac specific PTIP null (PTIP−) and control (PTIP+) mice. PTIP is part of a histone methyltransferase complex that imparts histone methylation marks that are associated with functionally active chromatin. Using PTIP+ and PTIP− mice, we identified target genes that may be regulated by their histone methylation status by performing gene expression arrays and qPCR. Array analysis revealed that 332 genes are significantly altered. The target genes identified include Kchip2 and Kv4.3, genes that regulate the cardiac repolarization gradient. ChIP for histone methylation marks revealed that PTIP deletion significantly decreases the histone methylation marks associated with actively expressed genes. Phenotypic analysis of PTIP− mice revealed that they have prolonged action potential durations with a decreased transient outward current and increased calcium transients resulting in improved contractility in vitro and improved systolic function in vivo. We conclude that histone methylation is critical for regulating the gene expression profile and electrophysiologic phenotype of adult differentiated tissue.
- © 2010 by American Heart Association, Inc.