Inhibition of H3K79me2 by DOT1L Inhibitor EPZ5676 Promotes Mouse Embryonic Lung Branching Morphogenesis via Increasing Epithelium Proliferation

ABSTRACT Histone modifications play a crucial role in regulating pulmonary branching morphogenesis, yet their specific contributions remain incompletely understood. Here, we demonstrate that H3K79me2 is broadly distributed throughout the airway epithelium in the early developmental stages of mouse embryonic lungs. Inhibition of H3K79me2 through EPZ5676, a DOT1L inhibitor, significantly enhanced branching morphogenesis in lung explant cultures. RNA‐seq analysis revealed that EPZ5676 promotes epithelial cell differentiation and proliferation. Notably, in mesenchyme‐free cultures, EPZ5676 alone did not influence epithelial morphogenesis but synergistically stimulated epithelial branching in the presence of FGF7. These findings identify H3K79me2 as a potential negative regulator of pulmonary branching morphogenesis and highlight the DOT1L inhibitor EPZ5676 as a promising epigenetic therapeutic molecule for promoting lung development and addressing pulmonary developmental disorders.