Histone H3K27me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism

Abstract

C r i b b s e t a l 2 SIGNIFICANCE STATEMENTThe precise regulation of Th17 cell metabolic function is central to an inflammatory response.Following activation, T cells undergo metabolic reprogramming and utilise up-regulated glycolysis to increase the availability of ATP. This work establishes an epigenetic link between the H3K27 demethylases KDM6A/B and the coordination of a metabolic response in activated Th17 cells.Inhibition of KDM6A/B leads to global increases in the repressive H3K27me3 histone mark resulting in down-regulation of key transcription factors, followed by metabolic reprogramming and the induction of anergy in Th17 cells. This work suggests a critical role of KDM6 enzymes in maintaining Th17 functions by controlling metabolic switches, necessary for T cells to adapt to their specific roles. C r i b b s e t a l 3 ABSTRACT T helper (T h ) cells are CD4+ effector T cells that play an instrumental 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, whereas in mature Th17 cells an altered transcriptional program leads to a profound metabolic reprogramming with concomitant suppression of IL-17 cytokine levels and reduced proliferation. Single cell analysis reveals a specific shift from highly inflammatory cell subsets towards a resting state upon demethylase inhibition. The apparent root cause of the observed anti-inflammatory phenotype in stimulated Th17 cells is reduced expression of key metabolic transcription factors, such as PPRC1 and c-myc. Overall, this leads to reduced mitochondrial biogenesis resulting in a metabolic switch with concomitant anti-inflammatory effects. These data are consistent with an opposing effect of GSK-J4 on Th17 T-cell differentiation pathways directly related to proliferation and effector cytokine profiles.

Inhibition of Histone H3K27 Demethylases Inactivates Brachyury (TBXT) and Promotes Chordoma Cell Death

“…This research reveals that treatment with H3K27 demethylases inhibitors alters a network of genes similar to those altered by knocking-down TBXT in chordoma cells, including genes involved in the cell cycle, production of extracellular matrix, growth factor and cytokine secretion, which are necessary for the survival of chordoma cells (20) and pertinent to notochord formation (20,30). Moreover, in keeping with our previous studies and that of others (28,39,51), we describe the activation of an ATF4-and DDIT3-driven stress response, thereby identifying this pathway as an additional possible therapeutic option for chordoma (45).…”

“…Such a strategy has been demonstrated successfully for oncogenes in other malignancies, for example repression of c-Myc with bromodomain and extra terminal domain (BET) protein inhibitors such as JQ1 in multiple myeloma (26), thereby circumventing the challenge of directly inhibiting transcription factors, which are often considered "undruggable" (50). Moreover, our previous work on human immune cell types such as macrophages, NK or T-cells (28,39,51) demonstrates reversible anti-proliferative and antiinflammatory effects upon GSK-J4 inhibition without signs of cell death, suggesting selective pro-apoptotic effects on cancer cells. This supports the concept that H3K27 demethylase inhibitors could potentially be used in the treatment of more common cancers which show a dependency on TBXT expression (18).…”

Genetic approaches to understand cellular responses to oxygen availability

“…This article is protected by copyright. All rights reserved KDM6A and KDM6B [11,97] which are both transcriptionally regulated by hypoxia, and function as ccRCC repressors [98]. It is thought that KDM6A is already downregulated in renal cancer cells, contributing to their hypersensitive EZH1 H3K27 methyltransferase activity [96].…”