Adult zebrafish robustly regenerate injured hearts through a complex orchestration of molecular and cellular activities. However, this remarkable process, which is largely non-existent in humans, remains incompletely understood. Here, we utilize integrated spatial transcriptomics (Stereo-seq) and single-cell RNA-sequencing (scRNA-seq) to generate a spatially-resolved molecular and cellular atlas of regenerating zebrafish heart across eight stages. We characterize the cascade of cardiomyocyte cell states responsible for producing regenerated myocardium and explore a potential role for tpm4a in cardiomyocyte re-differentiation. Moreover, we uncover the activation of ifrd1 and atp6ap2 genes as a unique feature of regenerative hearts. Lastly, we reconstruct a 4D “virtual regenerating heart” comprising 569,896 cells/spots derived from 36 scRNA-seq libraries and 224 Stereo-seq slices. Our comprehensive atlas serves as a valuable resource to the cardiovascular and regeneration scientific comm

Lekkos et al. show that a metabolic switch toward oxidative phosphorylation is required for cardiomyocyte re-differentiation and heart regeneration after injury in fish.

During organogenesis, precise pre-mRNA splicing is essential to assemble tissue architecture. Many developmentally essential exons bear weak 5'splice sites (5'SS) yet are spliced with high precision, ...

Nr2f transcription factors (TFs) are conserved regulators of vertebrate atrial cardiomyocyte (AC) di

CRISPR/Cas9 has massively accelerated the generation of gene loss-of-function models in zebrafish. H

Cardiomyocyte maturation is a core process in heart development. The study highlights the critical role of CXXC zinc finger protein 1 (Cfp1) in cardiomyocyte maturation and links its dysfunction to cardiac disease. The findings reveal that Cfp1 promotes cardiomyocyte maturation by regulating trimethylation on lysine 4 of histone H3 (H3K4me3) modification of adult genes, providing potential insights into the treatment of cardiac diseases. Abstract Cardiomyocyte maturation is the final stage of heart development, and abnormal cardiomyocyte maturation will lead to serious heart diseases. CXXC zinc finger protein 1 (Cfp1), a key epigenetic factor in multi-lineage cell development, remains underexplored in its influence on cardiomyocyte maturation. This study investigates the role and mechanisms of Cfp1 in this context. Cardiomyocyte-specific Cfp1 knockout (Cfp1-cKO) mice died within 4 weeks of birth. Cardiomyocytes derived from Cfp1-cKO mice showed an inhibited maturation phenotype, characterized by structural, metabolic, contractile, and cell cycle abnormalities. In contrast, cardiomyocyte-specific Cfp1 transgenic (Cfp1-TG) mice and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) overexpressing Cfp1 displayed a more mature phenotype. Mechanistically, deficiency of Cfp1 led to a reduction in trimethylation on lysine 4 of histone H3 (H3K4me3) modification, accompanied by the formation of ectopic H3K4me3. Furthermore, Cfp1 deletion decreased the level of H3K4me3 modification in adult genes and increased the level of H3K4me3 modification in fetal genes. Collectively, Cfp1 modulates the expression of genes crucial to cardiomyocyte maturation by regulating histone H3K4me3 modification, thereby intricately influencing the maturation process. This study implicates Cfp1 as an important molecule regulating cardiomyocyte maturation, with its dysfunction strongly linked to cardiac disease.