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

TLDR

Trained immunity sustains an enhanced innate immune response to secondary challenges through metabolic and transcriptional reprogramming. The authors hypothesize that the Set7 methyltransferase is a key regulator of β‑glucan‑induced trained immunity due to its links with metabolic memory and H3K4me1. Pharmacological studies of human primary monocytes reveal that Set7 controls trained‑immunity‑specific immunometabolic pathways, including a novel H3K4me1‑dependent plasticity in oxidative phosphorylation. Set7 drives trained immunity by modulating H3K4me1‑dependent oxidative phosphorylation and inducing gene expression changes associated with myelopoiesis progenitors, offering mechanistic insight into sustained metabolic alterations.

Abstract

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.