Kmt2c and Kmt2d histone methyltransferase deficiencies compromise macrophage function.

Methylation of histone (H) 3 lysine (K) 4 has a well-established role in innate immune responses, but the contribution of H3K4 methyltransferases Kmt2c and Kmt2d in innate immunity is incompletely understood. Using conditional knockout (KO) mouse models, we investigated how Kmt2c- and Kmt2d-deficiencies affect innate immune cell function. Through functional, transcriptomic, and metabolic analyses, we delineate the consequences of disrupted epigenetic regulation on macrophage biology. Our findings reveal that loss of Kmt2c or Kmt2d in macrophages leads to impaired pro-inflammatory cytokine response and phagocytotic capacity, as well as skewed energy metabolism towards glycolysis, highlighting the critical role of H3K4 methylation-dependent chromatin regulation in shaping innate immune cell behavior. This study provides the first comprehensive characterization of innate immune system dysfunction in mouse models with conditional Kmt2c and Kmt2d deletions and offers mechanistic insight into how epigenetic regulators control fundamental immune processes.