A Cardiac Transcriptional Enhancer is Repurposed During Regeneration to Activate an Anti-proliferative Program

Abstract

Previously, we discovered a gene regulatory element, called103runx1EN(or REN), capable of activating target gene expression throughout the heart during regeneration. REN also drives expression in uninjured cardiac tissue surrounding valves viewed from the reporter and phenotypes arising from a REN-deletion mutant. Activity of the REN reporter peaks just before and during the peak of regeneration. During this time, REN activity in myocardium adjacent to the valves goes away. The expression dynamics of the REN reporter, motifs embedded within REN and the fact that REN activates not just during injury but generally during cardiomyocyte proliferation all suggest that REN is an enhancer promoting regeneration. Unexpectedly, deletion ofRENresults in improved cardiomyocyte proliferation suggesting activation of anti-proliferative factors is part of the normal course of regeneration. REN is also active in the newly formed regenerated muscle during the conclusion of regeneration. Taken together, our findings support a model that in the zebrafish heart, an anti-proliferative gene expression program controls the spatiotemporal dynamics of cardiomyocyte proliferation.