Genetic Dissection of a Super Enhancer Controlling the <i>Nppa-Nppb</i> Cluster in the Heart

Rationale: ANP (atrial natriuretic peptide) and BNP (B-type peptide), encoded by the clustered genes Nppa Nppb , are important prognostic, diagnostic, therapeutic proteins in cardiac disease. The spatiotemporal expression pattern stress-induction of tightly regulated, possibly involving their coregulation an evolutionary conserved enhancer cluster. Objective: To explore physiological functions cluster elucidate genomic mechanism underlying Nppa-Nppb vivo. Methods Results: By analyzing epigenetic data we uncovered with super characteristics upstream . Using CRISPR/Cas9 genome editing, or parts thereof, flanking regions entire block spanning respectively, were deleted from mouse genome. impact on gene regulation phenotype respective lines was investigated transcriptomic, epigenomic, phenotypic analyses. essential for prenatal postnatal ventricular but not any other gene. Enhancer cluster–deficient mice showed enlarged hearts before after birth, similar to compound knockout generated. Analysis deletion alleles indicated engages promoters a competitive rather than cooperative mode, resulting increased when sequences deleted. maintained its active state selectivity target absent. In animals, induced remained low postmyocardial infarction border zone hypertrophic ventricle, regulatory proximal Conclusions: Coordinated is controlled manner shared enhancer, which also required augment stress-induced prevent premature hypertrophy.