Zebrafish heart regeneration after injury is dependent on the pro-regenerative environment provided by the epicardium, a thin layer of cells that surround the heart. While many of the genes involved in both development and regeneration have been identified, those specific to epicardial activation upon injury are less well described. Now, Yingxi Cao, Kenneth Poss, Jingli Cao and colleagues use chromatin accessibility data (ATAC-seq) and bulk transcriptome data from epicardial cells to identify regions of DNA that undergo chromatin remodelling with coincident gene expression changes upon heart injury. They identify potential tissue regeneration enhancer elements (TREEs), and confirm that many of them are associated with genes with known roles in heart regeneration, such as aldh1a2 and nrg1. The authors also validate the activity of TREEs associated with three genes not previously implicated in heart regeneration, which encode an adhesion molecule, NCAM; Rgmb, a TGFβ signalling component; and a G-protein, Gnai3. They find that both ncam1a and gnai3 are linked to multiple enhancer elements, and that these enhancers work additively (ncam1a enhancers) or redundantly (gnai3 enhancers). Together, these data provide a novel dataset of candidate pro-regenerative factors, as well as identifying three new candidate genes that may have broad roles in regeneration.