Histone H3K27me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism
Abstract: T helper (Th) cells are CD4+ effector T cells that play a critical role in immunity by shaping the inflammatory cytokine environment in a variety of physiological and pathological situations. Using a combined chemico-genetic approach, we identify histone H3K27 demethylases KDM6A and KDM6B as central regulators of human Th subsets. The prototypic KDM6 inhibitor GSK-J4 increases genome-wide levels of the repressive H3K27me3 chromatin mark and leads to suppression of the key transcription factor RORγt during Th17 differentiation. In mature Th17 cells, GSK-J4 induces an altered transcriptional program with a profound metabolic reprogramming and concomitant suppression of IL-17 cytokine levels and reduced proliferation. Single-cell analysis reveals a specific shift from highly inflammatory cell subsets toward a resting state upon demethylase inhibition. The root cause of the observed antiinflammatory phenotype in stimulated Th17 cells is reduced expression of key metabolic transcription factors, such as PPRC1. Overall, this leads to reduced mitochondrial biogenesis, resulting in a metabolic switch with concomitant antiinflammatory effects. These data are consistent with an effect of GSK-J4 on Th17 T cell differentiation pathways directly related to proliferation and include regulation of effector cytokine profiles. This suggests that inhibiting KDM6 demethylases may be an effective, even in the short term, therapeutic target for autoimmune diseases, including ankylosing spondylitis
- Location
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Deutsche Nationalbibliothek Frankfurt am Main
- Extent
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Online-Ressource
- Language
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Englisch
- Notes
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Proceedings of the National Academy of Sciences. - 117, 11 (2020) , 6056-6066, ISSN: 1091-6490
- Event
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Veröffentlichung
- (where)
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Freiburg
- (who)
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Universität
- (when)
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2024
- Creator
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Cribbs, Adam
Terlecki-Zaniewicz, Stefan
Philpott, Martin
Baardman, Jeroen
Ahern, David
Lindow, Morten
Obad, Susanna
Oerum, Henrik
Sampey, Brante
Mander, Palwinder K.
Penn, Henry
Wordsworth, Paul
Bowness, Paul
De Winther, Menno P. J.
Prinjha, Rab K.
Feldmann, Marc
Oppermann, Udo
- DOI
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10.1073/pnas.1919893117
- URN
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urn:nbn:de:bsz:25-freidok-2598126
- Rights
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
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15.08.2025, 7:23 AM CEST
Data provider
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Associated
- Cribbs, Adam
- Terlecki-Zaniewicz, Stefan
- Philpott, Martin
- Baardman, Jeroen
- Ahern, David
- Lindow, Morten
- Obad, Susanna
- Oerum, Henrik
- Sampey, Brante
- Mander, Palwinder K.
- Penn, Henry
- Wordsworth, Paul
- Bowness, Paul
- De Winther, Menno P. J.
- Prinjha, Rab K.
- Feldmann, Marc
- Oppermann, Udo
- Universität
Time of origin
- 2024
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Histone modifications regulate DNA replication coupled nucleosome assembly
Satb1 regulates the effector program of encephalitogenic tissue Th17 cells in chronic inflammation
Histone deacetylase inhibitors regulate the proteasomal degradation of oncoproteins
Histone deacetylase (HDAC) 1 and 2 complexes regulate both histone acetylation and crotonylation in vivo
Batf-dependent Th17 cells critically regulate IL-23 driven colitis-associated colon cancer
TNF-inhibitor drugs regulate human pathogenic Th17 cells through induction of IL-10
T cell-expressed microRNAs critically regulate T follicular helper and Th17 cells
Histone deacetylases regulate organ-specific growth in a horned beetle
Cyclic AMP induces reversible EPAC1 condensates that regulate histone transcription
KMT 1 family methyltransferases regulate heterochromatin–nuclear periphery tethering via histone and non‐histone protein methylation
Keratinocytes regulate the threshold of inflammation by inhibiting T cell effector functions
Th17 cytokines regulate profibrotic cytokines release by human eosinophils
Histone modifications regulate DNA replication coupled nucleosome assembly
Satb1 regulates the effector program of encephalitogenic tissue Th17 cells in chronic inflammation
Histone deacetylase inhibitors regulate the proteasomal degradation of oncoproteins
Histone deacetylase (HDAC) 1 and 2 complexes regulate both histone acetylation and crotonylation in vivo
Batf-dependent Th17 cells critically regulate IL-23 driven colitis-associated colon cancer
TNF-inhibitor drugs regulate human pathogenic Th17 cells through induction of IL-10
T cell-expressed microRNAs critically regulate T follicular helper and Th17 cells
Histone deacetylases regulate organ-specific growth in a horned beetle
Cyclic AMP induces reversible EPAC1 condensates that regulate histone transcription
KMT 1 family methyltransferases regulate heterochromatin–nuclear periphery tethering via histone and non‐histone protein methylation