Abstract
A major barrier to human heart regeneration is the absence of cardiomyocyte (CM) cell division in the infarcted heart. Remarkably, injured hearts of adult zebrafish and neonatal mice are capable of robust heart regeneration achieved through CM proliferation. Pontin is an evolutionarily conserved member of the AAA+ ATPase superfamily of proteins that regulates transcription, chromatin remodeling, and cell cycle progression in many contexts. Nonetheless, the involvement of Pontin in regulating CM proliferation has not been assessed. Using loss- and gain-of-function models in zebrafish and mice, we have determined that Pontin is necessary and sufficient for driving CM proliferation. Zebrafish pontin mutants are devoid of CM proliferation during heart development, and CM-specific overexpression of Pontin ( pontin OE ) is sufficient to induce myocardial hyperplasia during heart development and regeneration. In mice, myocardial-specific deletion of Pontin dampens CM proliferation, leading to embryonic lethality at E12.5, while CM-specific overexpression of Pontin from P0 to P7 is sufficient to increase the CM mitotic index. To decipher the molecular mechanism by which pontin OE stimulates CM proliferation, we performed single-cell ATAC + RNA-sequencing analysis of hyperproliferative pontin OE CMs during zebrafish regeneration. We identified significant downregulation of several anti-proliferative genes, including three in the btg/tob family ( btg1 , btg2 , tob1b ). The btg2 and tob1b loci showed reduced chromatin accessibility, suggesting that they could be direct targets of Pontin’s chromatin remodeling activity. We are currently testing this hypothesis and determining if overexpression of Pontin in neonatal mice extends the regenerative window beyond P7. In conclusion, our data highlight Pontin as a novel regulator of CM proliferation, potentially by controlling the chromatin accessibility of anti-proliferative genes.
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