Journal of Biological Chemistry
Volume 293, Issue 7, 16 February 2018, Pages 2422-2437
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Gene Regulation
Inhibition of histone H3K27 demethylases selectively modulates inflammatory phenotypes of natural killer cellsEpigenetic modulation of NK cell phenotypes

https://doi.org/10.1074/jbc.RA117.000698Get rights and content
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Natural killer (NK) cells are innate lymphocytes, important in immune surveillance and elimination of stressed, transformed, or virus-infected cells. They critically shape the inflammatory cytokine environment to orchestrate interactions of cells of the innate and adaptive immune systems. Some studies have reported that NK cell activation and cytokine secretion are controlled epigenetically but have yielded only limited insight into the mechanisms. Using chemical screening with small-molecule inhibitors of chromatin methylation and acetylation, further validated by knockdown approaches, we here identified Jumonji-type histone H3K27 demethylases as key regulators of cytokine production in human NK cell subsets. The prototypic JMJD3/UTX (Jumonji domain–containing protein 3) H3K27 demethylase inhibitor GSK-J4 increased global levels of the repressive H3K27me3 mark around transcription start sites of effector cytokine genes. Moreover, GSK-J4 reduced IFN-γ, TNFα, granulocyte–macrophage colony-stimulating factor (GM-CSF), and interleukin-10 levels in cytokine-stimulated NK cells while sparing their cytotoxic killing activity against cancer cells. The anti-inflammatory effect of GSK-J4 in NK cell subsets, isolated from peripheral blood or tissue from individuals with rheumatoid arthritis (RA), coupled with an inhibitory effect on formation of bone-resorbing osteoclasts, suggested that histone demethylase inhibition has broad utility for modulating immune and inflammatory responses. Overall, our results indicate that H3K27me3 is a dynamic and important epigenetic modification during NK cell activation and that JMJD3/UTX-driven H3K27 demethylation is critical for NK cell function.

histone demethylase
histone modification
enzyme inhibitor
epigenetics
natural killer cells (NK cells)
inhibitor

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This work was supported by Kennedy Trust for Rheumatology Research, Arthritis Research UK Program Grant 20522, the National Institute of Health Research Oxford Biomedical Research Unit, Cancer Research UK, and the Rosetrees Trust. This work is supported in part by Medical Research Council CGAT Program Grant G1000902 (to A. C.). The Structural Genomics Consortium is a registered charity (Number 1097737) that receives funds from Abbvie, Bayer Healthcare, Boehringer Ingelheim, the Canadian Institutes for Health Research, the Canadian Foundation for Innovation, Eli Lilly and Company, Genome Canada, the Ontario Ministry of Economic Development and Innovation, Janssen, the Novartis Research Foundation, Pfizer, Takeda, and the Wellcome Trust. The research leading to these results has received funding from the People Programme (Marie Curie Actions) of European Union Seventh Framework Programme FP7/2007–2013 under Research Executive Agency (REA) Grant Agreement 609305. The authors declare that they have no conflicts of interest with the contents of this article.

This article contains supporting information, Tables S1–S3, and Figs. S1–S3.

RNA-seq, ATACs-eq, and ChIP-seq data sets were deposited with the GEO database under accession number GSE89669.