H3K27me3-mediated silencing of structural genes is required for zebrafish heart regeneration

Deciphering the genetic and epigenetic regulation of cardiomyocyte proliferation in organisms, such as zebrafish, capable of robust cardiac renewal represents an attractive inroad towards regenerating the human heart. Using integrated high-throughput transcriptional and chromatin analyses, we identified a strong association between H3K27me3 deposition and reduced sarcomere and cytoskeletal gene expression in proliferative cardiomyocytes following injury. To move beyond an association, we generated an inducible transgenic strain expressing a mutant version of histone 3, H3.3K27M that inhibits H3K27me3 catalysis in cardiomyocytes during the regenerative window. Hearts comprised of H3.3K27M-expressing cardiomyocytes fail to regenerate with wound edge cells showing heightened expression of structural genes and prominent sarcomere structures. Although cell cycle re-entry was unperturbed, cytokinesis and wound invasion were significantly compromised. Collectively, our study identifies H3K27me3-mediated silencing of structural genes as requisite for zebrafish heart regeneration and suggests that repression of similar structural components in the border zone of infarcted human hearts might improve its regenerative capacity.