Zebrafish has become a powerful animal model for regenerative studies because of the capacity of its adult organ regeneration.Understanding the cellular and molecular mechanisms on zebrafish heart regeneration holds great potential for priming mammalian heart for regeneration.By RNA-Seq analyses,we identified several new signaling molecules for promoting heart regeneration in zebrafish.We have shown that Duox-generated H2O2 acts as a novel epicardial and myocardial signal to prime the heart for regeneration(Han et al.,2014 Cell Research).Injury-induced H2O2 destabilized the redox-sensitive phosphatase Dusp6 and hence increased the phosphorylation of Erk1/2,a convergent MAP kinase signaling pathway activated by growth factors such as FGF and PDGF.Second,we found that chromatin remodeling factor Brg1 is required for promoting heart regeneration in zebrafish(Diao et al.,2015 Developmental Biology; Xiao and Gao et al.,2016 under minor revision).Brg1 was induced during heart regeneration,and myocardial-specific ablation of Brg1 interfered with the formation of proliferating cardiomyocytes,leading to severe cardiac fibrosis and compromised myocardial regeneration.Mechanistically,Brg1 directly interacts with Dnmt3ab to induce methylation of the cdkn1c promoter and so suppress its mRNA expression.Conditional over-expression of pro-regenerative factor Brg1 promoted neonatal myocardial proliferation in mice.Furthermore,both H2O2 and Brg1 signaling pathways promote Tg(gata4:EGFP)-positive cardiac stem cells for heart regeneration.Ongoing works are particularly focusing on deciphering the molecular nature of adult cardiac progenitors during heart regeneration.Together,our works suggest that restoring Brg1 activity or repressing Dusp6 may offer new strategies for improving mammalian myocardial regeneration.