The Set7 Lysine Methyltransferase Regulates Plasticity in Oxidative Phosphorylation Necessary for Trained Immunity Induced by β-Glucan

Trained immunity confers a sustained augmented response of innate immune cells to a secondary challenge, via a process dependent on metabolic and transcriptional reprogramming. Because of its previous associations with metabolic and transcriptional memory, as well as the importance of H3 histone lysine 4 monomethylation (H3K4me1) to innate immune memory, we hypothesize that the Set7 methyltransferase has an important role in trained immunity induced by β-glucan. Using pharmacological studies of human primary monocytes, we identify trained immunity-specific immunometabolic pathways regulated by Set7, including a previously unreported H3K4me1-dependent plasticity in the induction of oxidative phosphorylation. Recapitulation of β-glucan training in vivo additionally identifies Set7-dependent changes in gene expression previously associated with the modulation of myelopoiesis progenitors in trained immunity. By revealing Set7 as a key regulator of trained immunity, these findings provide mechanistic insight into sustained metabolic changes and underscore the importance of characterizing regulatory circuits of innate immune memory. [Display omitted] •Set7 regulates enhanced cytokine production in trained immunity in vitro•Set7 knockout mice are unable to mount trained immunity against endotoxin challenge•Set7 modulates cellular respiration in β-glucan-trained macrophages•Set7-dependent histone methylation regulates MDH2 and SDHB in trained cells Using a combination of pharmacological and genetic approaches, Keating et al. show that the Set7 methyltransferase is a regulator of trained immunity induced by β-glucan. Activation of Set7 increases oxidative phosphorylation in trained cells via histone lysine methylation at gene enhancers of key enzymes of the TCA cycle.