Abstract 15971: Epigenetic Control of Adult Cardiac Myocyte Proliferation

Cardiac myocyte (CM) proliferation is required for the heart regeneration seen in lower vertebrates and neonatal mammalian injury models. However, typically mammalian CMs stop proliferating soon after birth and subsequent heart growth comes from hypertrophy, limiting the adult heart’s regenerative potential after injury. The molecular events blocking CM proliferation in the adult heart remain poorly understood. We hypothesized that trimethylation of Lysine 9 of Histone H3 (H3K9me3), a histone modification associated with stable transcriptional repression, is required for the silencing of cell cycle genes in adult CMs (ACMs). To test this, we developed a transgenic (BiTg) mouse model where H3K9me3 is specifically removed by histone demethylase KDM4D in CMs. Loss of H3K9me3 in CMs disrupts ACM cell cycle gene silencing preferentially and results in increased CM cycling. Normalized heart mass was increased by postnatal day 14 (P14) and continued to increase until 9-weeks of age. ACM number, but not size, was...