The hearts of adult zebrafish and neonatal mice have something in common: they can both regenerate remarkably well following injury, thanks to cardiomyocytes (CMs) that dedifferentiate and proliferate. As this capacity is severely restricted in adult humans, zebrafish can offer clues for how to enhance our own feeble heart regeneration. However, our understanding of the transcriptional and methylation control of zebrafish heart regeneration is still incomplete. Now, Tao Zhong and colleagues analyse the role of the Hairy-related bHLH transcriptional repressor Gridlock (also known as Hey2) in the regenerating zebrafish heart. grl is expressed throughout the adult myocardium, but expression is notably reduced in regenerating tissue. grl-deletion mutants display enhanced cardiac muscle regeneration following injury due to increased CM proliferation, and also show reduced fibrotic scarring. Conversely, inducing excess grl expression in the adult myocardium reduces the capacity of CMs to dedifferentiate and proliferate, and increases scarring. Grl directly inhibits expression of the lysine methyltransferase Smyd2 during regeneration, and Smyd2 is in turn identified as an enhancer of CM proliferation via methylation and activation of Stat3. Thus, Grl provides a break to zebrafish heart regeneration and, with Smyd2 and Stat3, represents a promising pathway to empower mammalian regeneration.
