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

Abstract

AbstractZebrafish have a high capacity to regenerate their hearts. Several recent studies have surveyed transcriptional enhancers to understand how the dynamics of gene expression are controlled during regeneration. Here, we describe an enhancer, calledREN, that controls expression around cardiac valves in uninjured hearts and is then repurposed for activating transcription in regenerating tissue. Interestingly, REN activity around valves is perfectly anti-correlated with the site of injury. Although,RENhas the hallmarks of activating a pro-regenerative program, deletion mutants have increased CM proliferation suggestingRENactivates an anti-proliferative program. We show thatRENis an essential enhancer forrunx1,a nearby gene that when mutated has similar increases in CM proliferation.RENmutants lack appreciable differences in cardiac scar formation, eliminating thisrunx1specific phenotype as a cause for the increased CM proliferation. Thus, the enhancer mutants revealed a more detailed model ofrunx1function than what could be appreciated from the gene mutant alone.RENdeletion mutants also had phenotypes in uninjured hearts, that we show is independent ofrunx1. Our data point to a new mechanism for gene control during zebrafish heart regeneration where an enhancer from one cardiac domain is repurposed to activate a different nearby gene at the site of regeneration.