Abstract 1915: Histone Methylation Regulates Gene Expression and Cardiac Function
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 and cardiac function 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 (PTIPnull) and control (PTIP+) mice. PTIP is part of a histone methyltransferase complex that imparts histone methylation marks that are associated with functionally active chromatin. Functional analysis of PTIPnull and PTIP+ mice by echocardiography revealed that PTIP deletion after tamoxifen injection induced a significant improvement in cardiac function as compared to littermate controls (Table⇓). This hyperdynamic cardiac function was sustained for at least 180 days. Echo did not reveal any differences in heart rate, LV chamber size, or wall thickness. Using PTIP+ and PTIPnull 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 contractile, potassium channel, and metabolic proteins. In order to study the mechanism whereby PTIP alters gene expression, ChIP was performed on PTIP+ and PTIPnull mice to assess the histone methylation status at several target gene specific loci. ChIP revealed that PTIP deletion significantly decreases the histone methylation marks associated with actively expressed genes. These results demonstrate that histone methylation plays a critical role in regulating the expression of functionally significant genes in adult cardiac myocytes. We conclude that histone methylation is critical for regulating the gene expression and phenotype of adult differentiated tissue.
This research has received full or partial funding support from the American Heart Association, National Center.