The Set7 Lysine Methyltransferase Regulates Plasticity in Oxidative Phosphorylation Necessary for Trained Immunity Induced by Beta-Glucan
47 Pages Posted: 3 Sep 2019 Publication Status: PublishedMore...
Trained immunity confers a sustained augmented response of innate immune cells to a secondary challenge, via a process dependent on metabolic and epigenetic reprogramming. Because of its previous associations to metabolic and epigenetic memory, as well as the importance of H3 histone lysine 4 monomethylation (H3K4me1) to innate immune memory, we hypothesized that the Set7 methyltransferase has an important role in trained immunity induced by the prototypical inducer of trained immunity β-glucan. Using pharmacological studies of human primary monocytes, we identified 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 revealed Set7-dependent changes in gene expression previously associated with the modulation of myelopoiesis progenitors in trained immunity. By revealing Set7 as an important epigenetic regulator of trained immunity, these findings provide mechanistic insight into metabolic changes and underscore the importance of characterizing key regulatory circuits of innate immune memory.
Keywords: Trained immunity, Set7, Methylation, β-glucan, oxidative phosphorylation, immunometabolism, inflammation, Monocyte, macrophage
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