AP-1 transcription factors in cardiomyocyte regeneration and repair

AP-1 transcription factors (TF) are a family of immediate early response genes whose expression is upregulated in response to multiple cellular stressors. More recent data have pointed to an important role of AP-1 TFs in regulating the chromatin accessibility landscape in a multitude of cell types. We observed significant enrichment of AP-1 motifs in regions of chromatin that become more accessible in regenerating zebrafish cardiomyocytes (CMs). Further analyses using a CM-specific dominant-negative approach revealed an essential role for AP-1 in CM dedifferentiation, proliferation, and invasion/repopulation into the injured collagenous scar (Beisaw et al., 2020).

Interestingly, AP-1 motifs were also enriched in regions of chromatin that become more accessible in border zone CMs of the nonregenerative adult mouse heart following myocardial infarction (van Duijvenboden et al., 2019). This discrepancy suggests that the AP-1 response differs in regenerative versus nonregenerative CMs. Understanding these differences may help us to direct adverse cardiac remodeling into a more reparative response. To support this hypothesis, we have shown that overexpression of Junb and Fosl1 (AP-1 members that are expressed in regenerating zebrafish CMs) in mammalian CMs in vitro can promote hallmarks of CM regeneration, including dedifferentiation, proliferation, and CM protrusion.