Evidence of Histone H2A.Z Deacetylation and Cardiomyocyte Dedifferentiation in Infarcted/Tip60-depleted Hearts.

Myocardial infarction (MI) in the human heart causes death of billions of cardiomyocytes (CMs), resulting in cardiac dysfunction that is incompatible with life or lifestyle. In order to re-muscularize injured myocardium, replacement CMs must be generated via renewed proliferation of surviving CMs. Approaches designed to induce proliferation of CMs after injury have been insufficient. Toward this end, we are targeting the Tip60 acetyltransferase, based on the rationale that its pleiotropic functions conspire to block the CM cell-cycle at several checkpoints. We previously reported that genetic depletion of Tip60 in a mouse model after MI reduces scarring, retains cardiac function, and activates the CM cell-cycle, although it is unclear whether this culminates in the generation of daughter CMs. For pre-existing CMs in the adult heart to resume proliferation, it is becoming widely accepted that they must first dedifferentiate, a process highlighted by loss of maturity, epithelial to mesenchymal transitioning (EMT), and reversion from fatty acid oxidation to glycolytic metabolism, accompanied by softening of the myocardial extracellular matrix. Findings in hematopoietic stem cells, and more recently in neural progenitor cells, have shown that Tip60 induces and maintains the differentiated state via site-specific acetylation of the histone variant H2A.Z. Here, we report that genetic depletion of Tip60 from naïve or infarcted hearts results in the near-complete absence of acetylated H2A.Z in CM nuclei, and that this is accordingly accompanied by altered gene expressions indicative of EMT induction, ECM softening, decreased fatty acid oxidation, and depressed expression of genes that regulate the TCA cycle. These findings, combined with our previous work, support the notion that because Tip60 has multiple targets that combinatorially maintain the differentiated state and inhibit proliferation, its transient therapeutic targeting to ameliorate the effects of cardiac injury should be considered.