Abstract 137: Ctcf is Essential for Transcriptome Regulation in the Healthy Heart

Abstract

Heart failure is a syndrome resulting from complex genetic predisposition and multiple environmental factors. It is well established that global changes in gene expression accompany the transition through hypertrophy and on to overt failure producing deterioration of function at the organ level. Unknown, however, are the global changes in chromatin structure that allows for pathological gene expression. The epigenetic factor CTCF is a ubiquitous protein thought to be involved in maintenance of chromatin microenvironments. We found that hypertrophic stimulation down-regulates CTCF in the heart, and CTCF expression is significantly correlated with heart size in disease across genetic backgrounds. To test this relationship further, we have generated an inducible cardiac-specific CTCF knockout animal. These animals quickly develop severe heart failure characterized by a dilated left ventricle, decreased ejection fraction, and reactivation of the fetal gene program. Our analysis of published CTCF ChIP-seq data performed in mouse heart has also shown CTCF binding peaks flanking the fetal genes. Furthermore, we have found that CTCF abundance at these sites changes after hypertrophic agonist isoproterenol treatment, suggesting that CTCF protects from the development of cardiac disease by regulating gene expression. We also used RNA-seq to compare the transcriptome of adult myocytes isolated from control, CTCF KO mice, and mice that underwent transverse aortic constriction (TAC) to induce heart failure. These analyses showed that CTCF depletion remodels gene expression in a manner that mimics aspects of the pathological transcriptome in heart failure. Our data demonstrate that precise control of CTCF levels is required for normal transcriptome regulation in the adult heart and that alterations in CTCF levels (either via genetic, pharmacologic or surgical techniques) lead to cardiac pathology.