A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response
Open accessAbstract
The jumonji (JMJ) family of histone demethylases are Fe2+- and α-ketoglutarate-dependent oxygenases that are essential components of regulatory transcriptional chromatin complexes. These enzymes demethylate lysine residues in histones in a methylation-state and sequence-specific context. Considerable effort has been devoted to gaining a mechanistic understanding of the roles of histone lysine demethylases in eukaryotic transcription, genome integrity and epigenetic inheritance, as well as in development, physiology and disease. However, because of the absence of any selective inhibitors, the relevance of the demethylase activity of JMJ enzymes in regulating cellular responses remains poorly understood. Here we present a structure-guided small-molecule and chemoproteomics approach to elucidating the functional role of the H3K27me3-specific demethylase subfamily (KDM6 subfamily members JMJD3 and UTX). The liganded structures of human and mouse JMJD3 provide novel insight into the specificity determinants for cofactor, substrate and inhibitor recognition by the KDM6 subfamily of demethylases. We exploited these structural features to generate the first small-molecule catalytic site inhibitor that is selective for the H3K27me3-specific JMJ subfamily. We demonstrate that this inhibitor binds in a novel manner and reduces lipopolysaccharide-induced proinflammatory cytokine production by human primary macrophages, a process that depends on both JMJD3 and UTX. Our results resolve the ambiguity associated with the catalytic function of H3K27-specific JMJs in regulating disease-relevant inflammatory responses and provide encouragement for designing small-molecule inhibitors to allow selective pharmacological intervention across the JMJ family.
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From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [122]
Up-regulation of Kdm6a/b and associated induction of clearance genes in response to apoptotic cells is reminiscent of Kdm6a/b induction and H3K27me3 demethylation at inflammatory gene loci during macrophage activation.
“The up-regulation of Kdm6a/b and the associated induction of clearance genes in response to apoptotic cells is reminiscent of the Kdm6a/b induction and H3K27me3 demethylation at inflammatory gene loci during macrophage activation27,28.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [28]
Work with a small-molecule inhibitor of KDM6A/B demethylase activity indicated that H3K27 demethylation, specifically KDM6A/B catalysis, is required for pro-inflammatory gene activation in human primary macrophages.
“recent studies using a small molecule-based inhibitor specifically targeting KDM6A/B demethylase activity revealed that H3K27 demethylation, and more specifically KDM6A/B catalytic activity, are critical determinants of pro-inflammatory gene activation in human primary macrophages28.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [28]
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- Authors
- Kruidenier, L., Chung, C.-W., Cheng, Z., Liddle, J., Che, K., Joberty, G., Bantscheff, M., Bountra, C., Bridges, A., Diallo, H., Eberhard, D., Hutchinson, S., Jones, E., Katso, R., Leveridge, M., Mander, P. K., Mosley, J., Ramirez-Molina, C., Rowland, P., Schofield, C. J., Sheppard, R. J., Smith, J. E., Swales, C., Tanner, R., Thomas, P., Tumber, A., Drewes, G., Oppermann, U., Patel, D. J., Lee, K., & Wilson, D. M.
- Affiliations
- GlaxoSmithKline (United Kingdom) (GB)
- Memorial Sloan Kettering Cancer Center (US)
- University of Oxford (GB)
- Pfizer (United States) (US)
- Corresponding author
- Wilson, David M.
- ORCID
- Venue
- Nature
- Published
- 2012-07-29
- Volume
- 488
- Issue
- 7411
- Pages
- 404-408
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4691848
- OpenAlex
- W2062927905
- Cited by
- 950
- References
- 26
- Citations by year
- 2026: 39 · 2025: 48 · 2024: 56 · 2023: 73 · 2022: 51 · 2021: 67 · 2020: 93 · 2019: 72 · 2018: 74 · 2017: 87 · 2016: 81 · 2015: 73 · 2014: 70 · 2013: 55 · 2012: 11
- FWCI
- 27.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Wellcome Trust (092809)
- Versus Arthritis (18358)
- Canadian Institutes of Health Research
- National Cancer Institute (P30CA008748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- JMJD3, KDM6A, H3K27me3 demethylation, small molecule inhibitors, chemoproteomics, structure-based drug design, macrophage inflammation, lipopolysaccharide, inflammatory cytokines
- MeSH terms
- Amino Acid Sequence, Animals, Cells, Cultured, Enzyme Inhibitors, Histones, Humans, Lysine, Macrophages, Methylation, Models, Molecular, Substrate Specificity, Tumor Necrosis Factor-alpha, Evolution, Molecular, Inhibitory Concentration 50, Catalytic Domain, Mice, Biocatalysis, Jumonji Domain-Containing Histone Demethylases
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