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

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The Set7 Lysine Methyltransferase Regulates Plasticity in Oxidative Phosphorylation Necessary for Trained Immunity Induced by Β-Glucan University of Southern Denmark The Set7 Lysine Methyltransferase Regulates Plasticity in Oxidative Phosphorylation Necessary for Trained Immunity Induced by β-Glucan Keating, Samuel T.; Groh, Laszlo; van der Heijden, Charlotte D.C.C.; Rodriguez, Hanah; dos Santos, Jéssica C.; Fanucchi, Stephanie; Okabe, Jun; Kaipananickal, Harikrishnan; van Puffelen, Jelmer H.; Helder, Leonie; Noz, Marlies P.; Matzaraki, Vasiliki; Li, Yang; de Bree, L. Charlotte J.; Koeken, Valerie A.C.M.; Moorlag, Simone J.C.F.M.; Mourits, Vera P.; Domínguez-Andrés, Jorge; Oosting, Marije; Bulthuis, Elianne P.; Koopman, Werner J.H.; Mhlanga, Musa; El-Osta, Assam; Joosten, Leo A.B.; Netea, Mihai G.; Riksen, Niels P. Published in: Cell Reports DOI: 10.1016/j.celrep.2020.107548 Publication date: 2020 Document version: Final published version Document license: CC BY-NC-ND Citation for pulished version (APA): Keating, S. T., Groh, L., van der Heijden, C. D. C. C., Rodriguez, H., dos Santos, J. C., Fanucchi, S., Okabe, J., Kaipananickal, H., van Puffelen, J. H., Helder, L., Noz, M. P., Matzaraki, V., Li, Y., de Bree, L. C. J., Koeken, V. A. C. M., Moorlag, S. J. C. F. M., Mourits, V. P., Domínguez-Andrés, J., Oosting, M., ... Riksen, N. P. (2020). The Set7 Lysine Methyltransferase Regulates Plasticity in Oxidative Phosphorylation Necessary for Trained Immunity Induced by β-Glucan. Cell Reports, 31(3), [107548]. https://doi.org/10.1016/j.celrep.2020.107548 Go to publication entry in University of Southern Denmark's Research Portal Terms of use This work is brought to you by the University of Southern Denmark. Unless otherwise specified it has been shared according to the terms for self-archiving. If no other license is stated, these terms apply: • You may download this work for personal use only. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying this open access version If you believe that this document breaches copyright please contact us providing details and we will investigate your claim. Please direct all enquiries to [email protected] Article The Set7 Lysine Methyltransferase Regulates Plasticity in Oxidative Phosphorylation Necessary for Trained Immunity Induced by b-Glucan Graphical Abstract Authors Samuel T. Keating, Laszlo Groh, Charlotte D.C.C. van der Heijden, ..., Leo A.B. Joosten, Mihai G. Netea, Niels P. Riksen Correspondence [email protected] In Brief Using a combination of pharmacological and genetic approaches, Keating et al. show that the Set7 methyltransferase is a regulator of trained immunity induced by b-glucan. Activation of Set7 increases oxidative phosphorylation in trained cells via histone lysine methylation at gene enhancers of key enzymes of the TCA cycle. Highlights d Set7 regulates enhanced cytokine production in trained immunity in vitro d Set7 knockout mice are unable to mount trained immunity against endotoxin challenge d Set7 modulates cellular respiration in b-glucan-trained macrophages d Set7-dependent histone methylation regulates MDH2 and SDHB in trained cells Keating et al., 2020, Cell Reports 31, 107548 April 21, 2020 ª 2020 The Author(s). https://doi.org/10.1016/j.celrep.2020.107548 Cell Reports Article The Set7 Lysine Methyltransferase Regulates Plasticity in Oxidative Phosphorylation Necessary for Trained Immunity Induced by b-Glucan Samuel T. Keating,1 Laszlo Groh,1 Charlotte D.C.C. van der Heijden,1 Hanah Rodriguez,2 Je´ ssica C. dos Santos,1 Stephanie Fanucchi,3,4 Jun Okabe,2 Harikrishnan Kaipananickal,2,5 Jelmer H. van Puffelen,1,6 Leonie Helder,1 Marlies P. Noz,1 Vasiliki Matzaraki,1 Yang Li,1,7 L. Charlotte J. de Bree,1,8,9 Valerie A.C.M. Koeken,1 Simone J.C.F.M. Moorlag,1 Vera P. Mourits,1 Jorge Domı´nguez-Andre´ s,1 Marije Oosting,1 Elianne P. Bulthuis,10 Werner J.H. Koopman,10 Musa Mhlanga,3 Assam El-Osta,2,5,11 Leo A.B. Joosten,1,12 Mihai G. Netea,1,13 and Niels P. Riksen1,14,* 1Department of Internal Medicine and Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands 2Epigenetics in Human Health and Disease, Department of Diabetes, Monash University, Melbourne, VIC, Australia 3Division of Chemical, Systems and Synthetic Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa 4Gene Expression and Biophysics Group, CSIR Biosciences, Pretoria, South Africa 5Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia 6Department for Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands 7Department of Computational Biology for Individualised Infection Medicine, Centre for Individualised Infection Medicine, Helmholtz Centre for Infection Research, Hannover Medical School, 30625 Hannover, Germany 8Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark 9Odense Patient Data Explorative Network, University of Southern Denmark/Odense University Hospital, Odense, Denmark 10Department of Biochemistry, Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands 11Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong City, Hong Kong SAR 12Department of Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania 13Department for Genomics and Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany 14Lead Contact *Correspondence: [email protected] https://doi.org/10.1016/j.celrep.2020.107548 SUMMARY bolic changes and underscore the importance of characterizing regulatory circuits of innate immune Trained immunity confers a sustained augmented memory. response of innate immune cells to a secondary challenge, via a process dependent on metabolic and transcriptional reprogramming. Because of INTRODUCTION its previous associations with metabolic and tran- A series of recent discoveries has uncovered how cells of the scriptional memory, as well as the importance of innate immune system such as monocytes and macrophages H3 histone lysine 4 monomethylation (H3K4me1) undergo functional reprogramming to mount a de facto immune to innate immune memory, we hypothesize that memory of an infectious or inflammatory injury by a process the Set7 methyltransferase has an important role called trained immunity, which facilitates augmented responses in trained immunity induced by b-glucan. Using to subsequent pathogenic encounters (Netea et al., 2020). In the pharmacological studies of human primary mono- context of infections or vaccination, trained immunity provides cytes, we identify trained immunity-specific beneficial heterologous effects by the enhanced cytokine immunometabolic pathways regulated by Set7, response to stimulation with non-related pathogens. Prototypi- including a previously unreported H3K4me1- cal stimuli of trained immunity include the fungal cell wall compo- b dependent plasticity in the induction of oxida- nent -glucan (Quintin et al., 2012) and the bacillus Calmette- tive phosphorylation. Recapitulation of b-glucan Gue´ rin (BCG) vaccine (Kleinnijenhuis et al., 2012). Recent atten- tion has also turned to endogenous drivers of inflammation as in- training in vivo additionally identifies Set7-depen- ducers of trained immunity (Bekkering et al., 2014; van der Valk dent changes in gene expression previously asso- et al., 2016). These stimuli shape innate immunological mem- ciated with the modulation of myelopoiesis pro- ories by reprogramming metabolic and transcriptional profiles genitors in trained immunity. By revealing Set7 as (Arts et al., 2016a; Cheng et al., 2014). a key regulator of trained immunity, these findings Posttranslational methylation of proteins conveys informa- provide mechanistic insight into sustained meta- tion to cellular pathways, including those that regulate gene Cell Reports 31, 107548, April 21, 2020 ª 2020 The Author(s). 1 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Figure 1. Set7 Is Associated with Trained Immunity Induced by b-Glucan (A) Graphical outline of in vitro training methods. Adherent monocytes (Mo) were stimulated with 1 mg/mL b-glucan or standard culture medium (RPMI) for 24 h (first stimulus), allowed to differentiate to macrophages (M4) for 5 days, and restimulated for 24 h with LPS or RPMI on day 6. (legend continued on next page) 2 Cell Reports 31, 107548, April 21, 2020 expression. In vitro experiments with pan-methyltransferase RESULTS inhibitors revealed the pivotal importance of this chemical modification for trained macrophages (Cheng et al., 2014; Set7 Expression and Activity Are Increased in Human Quintin et al., 2012). Changes in histone lysine methyl modifi- Primary Monocytes and Macrophages Stimulated with cations (H3 histones monomethylated [H3K4me1] or trimethy- b-Glucan lated [H3K4me3] at lysine 4) underlie b-glucan-induced trained To investigate the role of Set7, we adopted a previously immunity (Novakovic et al., 2016). Signaling factors derived described in vitro model of trained immunity using the fungal from local tissue environments play key roles in determining cell wall component b-glucan (Cheng et al., 2014). Adherent hu- macrophage fate, and evidence points to the role of enhancer man primary monocytes were incubated with culture
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