Novel Roles for the Transcriptional Repressor E4BP4 in Both Cardiac Physiology and Pathophysiology [4 mouse lines]

Circadian clocks temporally orchestrate biological processes critical for cellular/organ function. For example, the cardiomyocyte circadian clock modulates cardiac metabolism, signaling, and electrophysiology over the course of the day, such that, disruption of the clock leads to age-onset cardiomyopathy (through unknown mechanisms). Here, we report that genetic disruption of the cardiomyocyte clock results in chronic induction of the transcriptional repressor E4BP4. Importantly, E4BP4 deletion prevents age-onset cardiomyopathy following clock disruption. These studies also indicate that E4BP4 regulates both cardiac metabolism (eg, fatty acid oxidation) and electrophysiology (eg, QT interval). Collectively, these studies reveal that E4BP4 is a novel regulator of both cardiac physiology and pathophysiology. Overall design: Comparative gene expression profiling analysis of RNA-seq data for biventricular heart tissue isolated from 4 mouse lines: 1) cardiomyocyte-specific Bmal1 knockout (CBK; Bmal1flox/flox/MHCaCre+/-) and littermate control (Bmal1flox/flox/MHCaCre-/-) mice; 2) cardiomyocyte-specific E4bp4 knockout (CEK; E4bp4flox/flox/MHCaCre+/-) and littermate control (E4bp4flox/flox/MHCaCre-/-) mice; 3) cardiomyocyte-specific Bmal1/E4bp4 double knockout (CBK/CEK; Bmal1flox/flox/E4bp4flox/flox/MHCaCre+/-) and littermate control (Bmal1flox/flox/E4bp4flox/flox/MHCaCre-/-) mice; and 4) Cre recombinase control (MHCaCre+/-) and littermate wild-type mice. Individual Bmal1flox/flox, E4bp4flox/flox, and MHCaCre+/- mouse lines