Histone H2A.Z Deacetylation and Dedifferentiation in Infarcted/Tip60-depleted Cardiomyocytes.

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Myocardial infarction (MI) results in the loss of billions of cardiomyocytes (CMs), resulting in cardiac dysfunction. To re-muscularize injured myocardium, new CMs must be generated via renewed proliferation of surviving CMs. Approaches to induce proliferation of CMs after injury have been insufficient. Toward this end we are targeting the acetyltransferase Tip60, encoded by the Kat5 gene, based on the rationale that its pleiotropic functions combine to block CM proliferation at multiple checkpoints. We previously demonstrated that genetic depletion of Tip60 in a mouse model after MI reduces scarring, retains cardiac function, and activates the CM cell-cycle, although it remains unclear whether this culminates in the generation of daughter CMs. In order for pre-existing CMs in the adult heart to undergo proliferation, it has become 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 (ECM). Based on recently published findings that Tip60 induces and maintains the differentiated state of hematopoietic stem cells and neurons via site-specific acetylation of the histone variant H2A.Z, we assessed levels of acetylated H2A.Z and dedifferentiation markers after depleting Tip60 in CMs post-MI. We report that genetic depletion of Tip60 from CMs after MI results in the near obliteration of acetylated H2A.Z in CM nuclei, accompanied by the altered expression of genes indicative of EMT induction, ECM softening, decreased fatty acid oxidation, and depressed expression of genes that regulate the TCA cycle. In accord with the possibility that site-specific acetylation of H2A.Z maintains adult CMs in a mature state of differentiation, CUT&Tag revealed enrichment of H2A.Zac K4/K7 in genetic motifs and in GO terms respectively associated with CM transcription factor binding and muscle development/differentiation. Along with our previous findings, these results support the notion that Tip60 has multiple targets in CMs that combine to maintain the differentiated state and prevent proliferation.