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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: Published

See all articles by Samuel Keating

Samuel Keating

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

Laszlo Groh

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

Charlotte van der Heijden

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

Hanah Rodriguez

Monash University

Jessica Dos Santos

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

Stephanie Fanucchi

University of Cape Town (UCT) - Division of Chemical, Systems & Synthetic Biology

Jun Okabe

Monash University

Harikrishnan Kn

Monash University

Jelmer van Puffelen

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

Leonie Helder

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

Marlies Noz

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

Vasiliki Matzaraki

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

Yang Li

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

Charlotte de Bree

Statens Serums Institut - Research Center for Vitamins and Vaccines

Valerie Koeken

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

Simone Moorlag

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

Vera Mourits

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

Jorge Dominguez-Andres

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

Marije Oosting

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

Musa Mhlanga

University of Cape Town (UCT) - Division of Chemical, Systems & Synthetic Biology; University of Lisbon - Institute of Molecular Medicine

Assam El-Osta

Monash University

Leo Joosten

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

Mihai G. Netea

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

Niels Riksen

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

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Abstract

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

Suggested Citation

Keating, Samuel and Groh, Laszlo and van der Heijden, Charlotte and Rodriguez, Hanah and Dos Santos, Jessica and Fanucchi, Stephanie and Okabe, Jun and Kn, Harikrishnan and van Puffelen, Jelmer and Helder, Leonie and Noz, Marlies and Matzaraki, Vasiliki and Li, Yang and de Bree, Charlotte and Koeken, Valerie and Moorlag, Simone and Mourits, Vera and Dominguez-Andres, Jorge and Oosting, Marije and Mhlanga, Musa and El-Osta, Assam and Joosten, Leo and Netea, Mihai G. and Riksen, Niels, The Set7 Lysine Methyltransferase Regulates Plasticity in Oxidative Phosphorylation Necessary for Trained Immunity Induced by Beta-Glucan (August 29, 2019). Available at SSRN: https://ssrn.com/abstract=3444608 or http://dx.doi.org/10.2139/ssrn.3444608
This version of the paper has not been formally peer reviewed.

Samuel Keating

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

6525 GA Nijmegen
Netherlands

Laszlo Groh

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

6525 GA Nijmegen
Netherlands

Charlotte Van der Heijden

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

6525 GA Nijmegen
Netherlands

Hanah Rodriguez

Monash University

23 Innovation Walk
Wellington Road
Clayton, Victoria 3800
Australia

Jessica Dos Santos

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

6525 GA Nijmegen
Netherlands

Stephanie Fanucchi

University of Cape Town (UCT) - Division of Chemical, Systems & Synthetic Biology

Cape Town
South Africa

Jun Okabe

Monash University

23 Innovation Walk
Wellington Road
Clayton, Victoria 3800
Australia

Harikrishnan Kn

Monash University

23 Innovation Walk
Wellington Road
Clayton, Victoria 3800
Australia

Jelmer Van Puffelen

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

6525 GA Nijmegen
Netherlands

Leonie Helder

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

6525 GA Nijmegen
Netherlands

Marlies Noz

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

6525 GA Nijmegen
Netherlands

Vasiliki Matzaraki

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

6525 GA Nijmegen
Netherlands

Yang Li

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

6525 GA Nijmegen
Netherlands

Charlotte De Bree

Statens Serums Institut - Research Center for Vitamins and Vaccines

Denmark

Valerie Koeken

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

6525 GA Nijmegen
Netherlands

Simone Moorlag

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

6525 GA Nijmegen
Netherlands

Vera Mourits

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

6525 GA Nijmegen
Netherlands

Jorge Dominguez-Andres

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

6525 GA Nijmegen
Netherlands

Marije Oosting

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

6525 GA Nijmegen
Netherlands

Musa Mhlanga

University of Cape Town (UCT) - Division of Chemical, Systems & Synthetic Biology ( email )

Cape Town
South Africa

University of Lisbon - Institute of Molecular Medicine ( email )

R. Branca Edmée Marques
Lisbon, 1600-276
Portugal

Assam El-Osta

Monash University

23 Innovation Walk
Wellington Road
Clayton, Victoria 3800
Australia

Leo Joosten

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

6525 GA Nijmegen
Netherlands

Mihai G. Netea

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS)

6525 GA Nijmegen
Netherlands

Niels Riksen (Contact Author)

Radboud University Nijmegen - Radboud Institute of Molecular Life Sciences (RIMLS) ( email )

6525 GA Nijmegen
Netherlands

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