The histone methyltransferase DOT1L is a new epigenetic regulator of pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by rising incidence, high mortality, and limited treatment options. The pathogenesis of IPF is complex, and the role of epigenetic factors in its development remains largely unexplored. Recent studies have highlighted DOT1L (Disruptor of telomeric silencing-1 like), a histone H3K79 methyltransferase, as a contributor to the fibrotic response, although its exact role in IPF is still unclear. Elevated levels of DOT1L, H3K79me3, and profibrotic proteins have been observed in both in vivo and in vitro models of pulmonary fibrosis. Lentiviral-mediated knockdown of DOT1L or treatment with the DOT1L-specific inhibitor EPZ5676 mitigated the progression of bleomycin-induced pulmonary fibrosis in mice. Additionally, heterozygous DOT1L-deficient mice (Dot1l+/-) were less susceptible to pulmonary fibrosis, exhibiting reduced lung fibrosis phenotypes in vivo. Mechanistically, DOT1L modulated Pinometostat TGF-β1-induced fibroblast fibrosis by promoting H3K79me3 enrichment at the Jag1 gene promoter (encoding the Notch ligand Jagged1), thereby enhancing Jagged1 expression. This, in turn, activated Notch signaling, driving the fibrotic response. In summary, our findings identify DOT1L as an epigenetic regulator in lung fibrosis pathogenesis, revealing a mechanism where H3K79 trimethylation at the Jag1 promoter stimulates Notch signaling and promotes the expression of profibrotic proteins, thereby accelerating lung fibrosis.