Histone methylation activity of KMT2D is required for proliferative control of the developing lung.

KMT2D, the histone methyltransferase and core component of the COMPASS/MLL4 complex, has been implicated in developmental diseases such as Kabuki Syndrome, interstitial lung disease, and congenital diaphragmatic hernia, with clear links to pediatric pulmonary disorders. Despite this, the mechanism by which KMT2D governs lung development remains unclear. Knock-in mouse models rendering, KMT2D catalytically deactivated (KMT2D KI ) and reducing H3K4 methylation, have demonstrated potential in defining KMT2D's role in pulmonary development. Our examination of the lungs of KMT2D KI mice revealed increased cellular density and impaired sacculation indicated by reduced airspace chord length, thickening of intersaccular septa, and abnormal alveolar cell differentiation. KMT2D KI mice revealed narrowed Sox2+ conducting airways and epithelial differentiation defects characterized by reduced Cc10+ club cells. Accompanying the alveolar and airway hypoplasia, blood vessel luminal area was reduced. Conversely, KMT2D KI lungs had a significantly higher proportion of proliferating cells accompanied by a dramatic expansion in Pdgfrα+ mesenchymal progenitor cells. Our findings therefore suggest that KMT2D-mediated H3K4 methylation is vital to normal lung development, and its impairment results in widespread pulmonary hypoplasia and potentially pulmonary hypertension.