John W. Lough, PhD

Dr. Lough’s current research is in collaboration with Dr. John Auchampach, Pharmacology & Toxicology, addressing whether the Tip60 protein is a pharmaceutical target in the heart, inactivation of which permits cardiac regeneration after a myocardial infarction (MI). Tip60 (Tat-interactive protein 60 kD) is an acetyltransferase that his laboratory has shown to be essential for embryonic development (Hu et al. 2009), and which suppresses cell-cycle activation while promoting apoptosis in cardiomyocytes of the adult heart (Fisher et al. 2012). Because these findings suggested that inhibition of Tip60 in the infarcted heart might promote regeneration by re-activating the cardiomyocyte cell-cycle, his laboratory designed a mouse model wherein the gene encoding Tip60 (termed Kat5) can be temporally and specifically depleted in cardiomyocytes (Fisher et al. 2016). Using this model, his laboratory’s recently published work has revealed, in both the neonatal (Wang et al., 2021) and the adult heart (Wang et al., 2022), that depletion of Tip60 after MI reduces apoptosis, limits scarring, and induces dedifferentiation, permitting renewed activation of the cardiomyocyte cell-cycle, all concomitant with the maintenance of cardiac function as determined by echocardiography. Most recently, the beneficial effects of depleting the Kat5 gene post-MI have been shown to be mimicked by administering drugs that inhibit Tip60’s acetyltransferase activity, including TH1834 (Wang et al., 2023) and pentamidine (manuscript in preparation).

At the molecular level, experiments described in the above publications indicate that the beneficial response to depleting Tip60 is mediated by abrogation of the DNA damage response (DDR), via reduced levels of phosphorylated Atm and the cell-cycle inhibitor p27, proteins known to be major obstacles to cardiomyocyte proliferation. Currently, the heart regeneration field accepts the notion that in order for cardiomyocytes to re-enter the cell cycle and resume proliferation, they must first become ‘dedifferentiated’, a process consistent with our findings. In this regard, exciting work in other laboratories has recently shown that Tip60 is required to maintain the differentiated state in cell types including skeletal and smooth muscle, hematopoietic stem cells (HSCs), and neurons, by maintaining acetylation of the histone variant protein H2A.Z. In this regard we are extremely excited about our most recent findings showing that acetylation of H2A.Z is nearly completely extinguished when the Kat5 gene is depleted, suggesting that Tip60 regulates the differentiated state in cardiomyocytes. We are further investigating this possibility via an experimental strategy that includes CUT&Tag, to assess whether cardiomyogenic transcription factors recruit Tip60 to enhancer/promoter loci of genes responsible for cardiomyocyte maturity, wherein it maintains their expression by maintaining a bivalent activation signature comprised of H3K4me3 and acetylated H2A.Z.