The Set7 Lysine Methyltransferase Regulates Plasticity in Oxidative Phosphorylation Necessary for Trained Immunity Induced by β-Glucan
Samuel T. Keating, Laszlo Groh, Charlotte D.C.C. van der Heijden, Hanah Rodriguez, Jéssica Cristina dos Santos, Stephanie Fanucchi, Jun Okabe, Harikrishnan Kaipananickal, Jelmer H. van Puffelen, Leonie Helder, Marlies P. Noz, Vasiliki Matzaraki, Yang Li, L. Charlotte J. de Bree, Valerie A. C. M. Koeken, Simone J.C.F.M. Moorlag, Vera P. Mourits, Jorge Domínguez‐Andrés, Marije Oosting, Elianne P. Bulthuis, Werner J.H. Koopman, Musa M. Mhlanga, Assam El‐Osta, Leo A. B. Joosten, Mihai G. Netea, Niels P. Riksen
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.