Regional differences in cardiomyocyte automaticity permit the sinoatrial node (SAN) to function as the leading cardiac pacemaker and the atrioventricular (AV) junction as a subsidiary pacemaker. The regulatory mechanisms controlling the distribution of automaticity within the heart are not understood. To understand regional variation in cardiac automaticity, we carried out an in vivo analysis of cis-regulatory elements that control expression of the hyperpolarization-activated cyclic-nucleotide gated ion channel 4 (Hcn4). Using transgenic mice, we found that spatial and temporal patterning of Hcn4 expression in the AV conduction system required cis-regulatory elements with multiple conserved fragments. One highly conserved region, which contained a myocyte enhancer factor 2C (Mef2C) binding site previously described in vitro, induced reporter expression specifically in the embryonic non-chamber myocardium and the postnatal AV bundle in a Mef2c-dependent manner in vivo. Inhibition of histone deacetylase (HDAC) activity in cultured transgenic embryos showed expansion of reporter activity to working myocardium. In adult animals, hypertrophy induced by transverse aortic constriction, which causes translocation of HDACs out of the nucleus, resulted in ectopic activation of the Hcn4 enhancer in working myocardium, recapitulating pathological electrical remodeling. These findings reveal mechanisms that control the distribution of automaticity among cardiomyocytes during development and in response to stress.
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