Proliferative control of the saccular-stage developing mouse lung requires the histone methylation activity of KMT2D

Abstract

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 harboring catalytically inactive KMT2D (KMT2D KI ), thereby reducing H3K4 methylation, have demonstrated potential in defining KMT2D’s role in pulmonary development. Our post-hoc examination of the E18.5 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.