Leveraging chromatin state transitions for regulatory networks identification in heart regeneration

The limited regenerative capacity of the human heart is responsible for the high morbidity and mortality world-wide. In contrast, zebrafish possess a robust regenerative capacity. Here, we have characterized the chromatin state transitions during zebrafish heart regeneration and interrogated how gene expression patterns are orchestrated. We found a massive gain of repressive chromatin marks one day after myocardial injury, followed by a large-scale acquisition of active chromatin characteristics on day 4 and a switch to a repressive state on day 14. The correlative analysis predicted known and less well-characterized transcription factors and transcription factor ensembles involved in these transitions and classified them into activators or repressors of specific gene expression programs. Detailed analysis revealed that rapid transcriptional responses involved in extracellular matrix reorganization and TOR signaling involve the engagement of super-enhancers, while H3K4me3 breadth highly correlates with transcriptional activity and the dynamic transcriptional changes at genes involved in proteolysis, cell cycle activity, and cell differentiation. Finally, we detected significant evolutionary conservation between the regulatory regions that drive zebrafish and neonatal mouse regeneration, suggesting that reactivation of transcriptional and epigenetic networks converging on these conserved elements might unlock the regenerative potential of adult human hearts Cryoinjury was performed in adlt zebrafish heart and crosslinked chromatin was used to perform ChIP-seq at different time points