Similar Datasets
Project description:T helper (Th) 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, including autoimmune conditions such as ankylosing spondylitis. Here we identify KDM6A/KDM6B histone H3K27 demethylases by inhibitor and knockdown approaches as central regulators of human Th1, Th2 and Th17 subsets and establish a direct link between KDM6A/KDM6B in regulating Th17 cell metabolism. In mature Th17 cells demethylase inhibition leads to suppression of IL-17 cytokine levels and reduced proliferation through a pronounced ATF4 driven metabolic stress response in T cells derived from PBMC fractions of healthy donors and patients with ankylosing spondylitis. Metabolomic analyses reveal that Th17 T-cell differentiation is associated with an increase in glycolytic metabolism, pentosephosphate pathway activity and protein glycosylation intermediates. GSK-J4 treatment was shown to be overtly impactful on the cellular biochemistry of Th17 differentiated T-cells, with prominent effects on differentiation-related changes in glucose utilization, anabolic processes, and a remarkable change in amino acid and TCA cycle metabolism. During differentiation from naïve Th precursors to mature Th17 populations, demethylase inhibition with the prototypic inhibitor GSK-J4 leads to increases of repressive H3K27me3 chromatin marks, thereby down-regulating the required TH17 key transcription factor RORC and effectively suppressing metabolic reprogramming from a naïve T cell ground state to a differentiated subset. 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.
2020-02-13 | GSE126991 | GEO
Project description:T helper (Th) 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, including autoimmune conditions such as ankylosing spondylitis. Here we identify KDM6A/KDM6B histone H3K27 demethylases by inhibitor and knockdown approaches as central regulators of human Th1, Th2 and Th17 subsets and establish a direct link between KDM6A/KDM6B in regulating Th17 cell metabolism. In mature Th17 cells demethylase inhibition leads to suppression of IL-17 cytokine levels and reduced proliferation through a pronounced ATF4 driven metabolic stress response in T cells derived from PBMC fractions of healthy donors and patients with ankylosing spondylitis. Metabolomic analyses reveal that Th17 T-cell differentiation is associated with an increase in glycolytic metabolism, pentosephosphate pathway activity and protein glycosylation intermediates. GSK-J4 treatment was shown to be overtly impactful on the cellular biochemistry of Th17 differentiated T-cells, with prominent effects on differentiation-related changes in glucose utilization, anabolic processes, and a remarkable change in amino acid and TCA cycle metabolism. During differentiation from naïve Th precursors to mature Th17 populations, demethylase inhibition with the prototypic inhibitor GSK-J4 leads to increases of repressive H3K27me3 chromatin marks, thereby down-regulating the required TH17 key transcription factor RORC and effectively suppressing metabolic reprogramming from a naïve T cell ground state to a differentiated subset. 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.
2020-02-13 | GSE128008 | GEO
Project description:T helper (Th) 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, including autoimmune conditions such as ankylosing spondylitis. Here we identify KDM6A/KDM6B histone H3K27 demethylases by inhibitor and knockdown approaches as central regulators of human Th1, Th2 and Th17 subsets and establish a direct link between KDM6A/KDM6B in regulating Th17 cell metabolism. In mature Th17 cells demethylase inhibition leads to suppression of IL-17 cytokine levels and reduced proliferation through a pronounced ATF4 driven metabolic stress response in T cells derived from PBMC fractions of healthy donors and patients with ankylosing spondylitis. Metabolomic analyses reveal that Th17 T-cell differentiation is associated with an increase in glycolytic metabolism, pentosephosphate pathway activity and protein glycosylation intermediates. GSK-J4 treatment was shown to be overtly impactful on the cellular biochemistry of Th17 differentiated T-cells, with prominent effects on differentiation-related changes in glucose utilization, anabolic processes, and a remarkable change in amino acid and TCA cycle metabolism. During differentiation from naïve Th precursors to mature Th17 populations, demethylase inhibition with the prototypic inhibitor GSK-J4 leads to increases of repressive H3K27me3 chromatin marks, thereby down-regulating the required TH17 key transcription factor RORC and effectively suppressing metabolic reprogramming from a naïve T cell ground state to a differentiated subset. 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.
2020-02-13 | GSE127766 | GEO
Project description: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.
| S-EPMC7084125 | biostudies-literature
Project description:Histone H3K27 demethylases regulate human Th17 cell maturation and effector functions by impacting on metabolism
| PRJNA525356 | ENA
Project description:Histone H3K27 demethylases regulate human Th17 cell maturation and effector functions by impacting on metabolism [II]
| PRJNA525357 | ENA
Project description:Histone H3K27 demethylases regulate human Th17 cell maturation and effector functions by impacting on metabolism [I]
| PRJNA524108 | ENA
Project description:Histone H3K27 demethylases regulate human Th17 cell maturation and effector functions by impacting on metabolism [III]
| PRJNA526044 | ENA
Project description:The histone H3K27 demethylases UTX and JMJD3 are important regulatory factors that modulate gene expression by altering the physical state of chromatin. Previous studies have indicated an abnormal H3K27 methylation status in carcinogenesis. We therefore investigated the expression patterns of UTX and JMJD3 in renal cell carcinoma (RCC) and their roles in cancer development.The mRNA expression levels of the UTX and JMJD3 genes were determined in cancer tissues and adjacent normal tissues in 36 patients with primary RCC, using quantitative real-time-polymerase chain reaction. The UTX and JMJD3 protein contents were measured by western blotting and immunohistochemical analysis.UTX and JMJD3 transcripts were significantly increased in cancer tissues compared to normal tissues (P?<?0.05). mRNA levels of the inhibitor of cyclin-dependent kinases 4 and 6 p16INK4a were also increased in cancer tissues (P?<?0.001). Western blotting indicated that levels of both demethylases were increased in cancer tissues. The level of tri-methylated H3K27 (H3K27me3) was lower in cancer tissues compared to normal tissues, but expression of the H3K27 methyltransferase EZH2 was increased (P?<?0.05). These results suggest that the two H3K27 demethylases may play critical roles in the regulation of H3K27 methylation status in RCC. Immunohistochemical analysis confirmed that UTX and JMJD3 expression were upregulated in cancer tissues compared to adjacent tissues.This study demonstrated that UTX and JMJD3 were upregulated in cancer tissues, suggesting that they may be involved in the development of primary RCC. The potential roles of H3K27 demethylases as biomarkers in the early diagnosis of RCC need to be further explored.
| S-EPMC3520868 | biostudies-other
Project description: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-?, TNF?, 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.
| S-EPMC5818173 | biostudies-literature