AP-1 Regulates Chromatin Accessibility to Promote Sarcomere Disassembly and Cardiomyocyte Protrusion during Zebrafish Heart Regeneration

The zebrafish has emerged as a powerful model to study cardiac regeneration; however, the mechanisms by which cardiomyocytes respond to damage by disassembling sarcomeres, proliferating, and repopulating the injured area remain unclear. Here, we show that AP-1 transcription factors play an essential role in regulating the cardiomyocyte response. Using ATAC-Seq, we first find that the cardiomyocyte chromatin accessibility landscape is dynamic following cryoinjury, and that AP-1 motifs are the most highly enriched in regions that gain accessibility during regeneration. Using a cardiomyocyte-specific dominant-negative approach, we show that AP-1 promotes cardiomyocyte proliferation as well as chromatin accessibility at genes regulating sarcomere disassembly and cardiomyocyte protrusion into the injured area. We further find distinct temporal requirements for AP-1 during cardiac regeneration. Altogether, these results indicate that AP-1 plays a key role in the cardiomyocyte response to injury by promoting chromatin accessibility changes, allowing the activation of gene expression programs that support regeneration. Cardiomyocyte(CM)-specific ATAC-Seq from uninjured FACS sorted myl7:nucDsRed+ CMs (2x replicates), regenerating FACS sorted gata4:EGFP+ CMs at 4 days post cryoinjury (dpci, 2x replicates), dominant-negative A-Fos (+) wound border CMs at 4 dpci (3x replicates), A-Fos (-) wound border CMs at 4 dpci (3x replicates), uninjured junba overexpressing CMs (2x replicates), and uninjured junbb overexpressing CMs (2x replicates)