Background: Heart attacks in patients cause by permanent loss of heart muscle cells (cardiomyocytes), often leading to heart failure. In contrast, zebrafish and some other teleost fishes can regenerate their hearts after injury and understanding of the regenerative processes provides therapeutic opportunities for patients. This project aims to systematically investigate the molecular mechanisms underlying fish heart regeneration through multi-omics analysis, identify key regulators and verify their functions using gene editing. To obtain an overview of genetic mechanisms of regeneration, various sequencing datasets of healthy and post-injury fish hearts were analysed, including: quantitative trait loci (QTL), bulk RNA-seq, scRNA-seq, ATAC-seq, ChIP-seq, microRNA datasets. Especially, we performed cross-species scRNA-seq integration of healthy and cryo-injured hearts to compare non-regenerative and regenerative species on the cellular level. For better comparisons, we performed molecular pathway enrichment to fully utilise the homology between species.

As results, we identified several cavefish post-injury molecular phenotypes related with a high QTL signal region. In this region, distinct RNA variations were detected in several genes involved in the physiological activities of cardiomyocytes, which are promising targets for functional validation. Also, cross-species scRNA integration identified homologous fish cardiomyocytes subsets, which revealed distinct subset-level post-injury response of regenerative and non-regenerative species and identified key differential pathways. In conclusion so far, we identified several potential key regulators of fish heart regeneration. Cross-species integration identified cardiomyocytes subsets that differ in stemness and molecular functions, which can be used to construct a regulation network controlling regeneration and provide insights in improving cardiac repair in humans..