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Selective modulation of inflammatory Natural Killer (NK) cell phenotypes following histone H3K27 demethylase inhibition [ATAC-Seq and ChIP-Seq]

ABSTRACT: Natural Killer cells are innate lymphocytes, participate in immune surveillance and elimination of stressed or transformed cells and critically shape the inflammatory cytokine environment to interact with cells of the innate and adaptive immune system, including macrophages, dendritic and Tcells. By performing a focused compound library screening, further validated by knockdown approaches, we here identify Jumonji-type histone 3 lysine 27 (H3K27) demethylases as key regulators of cytokine production in various human NK cell subsets. The prototypic H3K27 demethylase inhibitor GSK-J4 increases global levels of the repressive H3K27me3 mark around transcription start sites including NK cell effector cytokines, and thereby reduces IFN-γ, TNF, GM-CSF and IL-10 levels in IL-15 stimulated NK cells whilst sparing the cytotoxic killing capacity against cancer cells. The anti-inflammatory effect of GSK-J4 in highly inflammatory NK cell subsets, isolated from peripheral blood or tissue from rheumatoid arthritis patients, coupled with an inhibitory effect on formation of bone-resorbing osteoclasts, suggests a wider role and utility of histone demethylase inhibition in immunity and inflammation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE89668 | GEO | 2018/02/28

REPOSITORIES: GEO

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Selective modulation of inflammatory Natural Killer (NK) cell phenotypes following histone H3K27 demethylase inhibition [RNA-Seq]

Project description:Natural Killer cells are innate lymphocytes, participate in immune surveillance and elimination of stressed or transformed cells and critically shape the inflammatory cytokine environment to interact with cells of the innate and adaptive immune system, including macrophages, dendritic and Tcells. By performing a focused compound library screening, further validated by knockdown approaches, we here identify Jumonji-type histone 3 lysine 27 (H3K27) demethylases as key regulators of cytokine production in various human NK cell subsets. The prototypic H3K27 demethylase inhibitor GSK-J4 increases global levels of the repressive H3K27me3 mark around transcription start sites including NK cell effector cytokines, and thereby reduces IFN-γ, TNFα, GM-CSF and IL-10 levels in IL-15 stimulated NK cells whilst sparing the cytotoxic killing capacity against cancer cells. The anti-inflammatory effect of GSK-J4 in highly inflammatory NK cell subsets, isolated from peripheral blood or tissue from rheumatoid arthritis patients, coupled with an inhibitory effect on formation of bone-resorbing osteoclasts, suggests a wider role and utility of histone demethylase inhibition in immunity and inflammation.

2018-02-28 | GSE89484 | GEO

A novel synthetic jumonji H3K27 demethylase inhibitor GSK-J4 exert immunosuppressive activities

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KDM6 Inhibition induces DNA Damage Response (DDR) during ESC Differentiation but not during self-renewal.

Project description:The discovery of the first histone demethylase in 2004 (LSD1/KDM1) opened new avenues for the understanding of how histone methylation impacts cellular functions. A great number of histone demethylases have been identified since, which are potentially linked to gene regulation as well as to stem cell self-renewal and differentiation. KDM6A/UTY and KDM6B/JMJD3 are both H3K27me3/2-specific histone demethylases, which are known to play a central role in regulation of posterior development, by regulating HOX gene expression. So far nothing is known about the role of histone lysine demethylases (KDMs) during early hematopoiesis. We are studying the role of KDM6A and KDM6B on self-renewal, global gene expression and on local and global chromatin states in embryonic stem cells (ESCs) and during differentiation. In order to completely abrogate KDM6 demethylase activity in ESCs we employed a specific inhibitor (GSK-J4, Kruidenier et al. 2012). Treatment of ESCs with GSK-J4 had no effect on viability and proliferation . However, ESC differentiation in the presence of GSK-J4 was completely abrogated. In conclusion we show that ESC differentiation is completely blockend in the absence of any H3K27 demethylase activity. We used microarrays to detail the global gene expression program of genes which are differentially expressed during the early differentiation of ESC derived embryoid bodies (EBs) in the presence of GSK-J4 (KDM6 Inhibitor). ESCs (R1) have been cultured and differentiated in the presence of GSK-J4 a KDM6 specific inhibitor.

2016-03-11 | E-GEOD-49886 | biostudies-arrayexpress

Histone H3K27 demethylases regulate human Th17 cell maturation and effector functions by impacting on metabolism [III]

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

Histone H3K27 demethylases regulate human Th17 cell maturation and effector functions by impacting on metabolism [II]

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Histone H3K27 demethylases regulate human Th17 cell maturation and effector functions by impacting on metabolism [I]

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RNA sequencing reveals resistance of TLR4 ligand-activated microglial cells to inflammation mediated by the selective jumonji H3K27 demethylase inhibitor

Project description:Persistent microglia activation is associated with the production and secretion of various pro-inflammatory genes, cytokines and chemokines, which may initiate or amplify neurodegenerative diseases. A novel synthetic histone 3 lysine 27 (H3K27) demethylases JMJD3 inhibitor, GSK-J4, was proven to exert immunosuppressive activities in macrophages. However, a genome-wide search for GSK-J4 molecular targets has not been undertaken in microglia. To study the immuno-modulatory effects of GSK-J4 on a transcriptomic level, triplicate RNA sequencing and quantitative real-time PCR analyses were performed with resting, GSK-J4, LPS and LPS+GSK-J4 challenged primary microglial (PM) and BV-2 microglial cells. Among the annotated genes, transcriptional sequencing of microglia that were treated with GSKJ4 revealed a selective effect on LPS induced gene expression in which the induction of cytokines/chemokines, interferon-stimulated genes, and prominent (transcription factors) TFs as well as previously unidentified genes that are important in inflammation was suppressed. Furthermore, we show that GSK-J4 controls important inflammatory genes targets by modulating STAT1, IRF7, and H3K27me3 level at their promoter site. These unprecedented results demonstrate the histone demethylases inhibitor GSK-J4 could have therapeutic applications for neuroinflammatory diseases.

2017-08-31 | GSE89817 | GEO

KDM6 Inhibition induces DNA Damage Response (DDR) during ESC Differentiation but not during self-renewal.

2016-03-11 | GSE49886 | GEO

RNA-seq of GSK-J4 Treated Neuroblastoma Cell Lines

Project description:High-risk neuroblastoma is often distinguished by amplification of MYCN and loss of differentiation potential with tumors refractory to retinoic acid differentiation based therapies. Here, we leverage high-throughput drug screening of epigenetic targeted therapies across a large and diverse tumor cell line panel to uncover the hypersensitivity of neuroblastoma cells to GSK-J4, a small molecule dual inhibitor of H3K27 demethylases UTX and JMJD3. Mechanistically, GSK-J4 induced neuroblastoma differentiation and ER stress with accompanying upregulation of PUMA and apoptosis induction. Retinoic acid (RA)-resistant neuroblastoma cells were sensitive to GSK-J4. Additionally, GSK-J4 was effective at blocking the growth of chemorefractory and patient-derived xenograft models of high-risk neuroblastoma in vivo. Further, GSK-J4 and RA combined to induce differentiation, ER-stress and limit the growth of neuroblastomas resistant to either drug alone. In MYCN-amplified neuroblastoma, which is the most prevalent driver gene alteration in the refractory population, PUMA induction by GSK-J4 sensitized tumors to the BCL-2 inhibitor venetoclax, demonstrating that epigenetic targeted therapies and BH3 mimetics can be rationally combined to treat high-risk subset of neuroblastoma. Therefore, H3K27 demethylation inhibition is a promising therapeutic target to treat high-risk neuroblastoma, and H3K27 demethylation can be part of rational combination therapies to induce robust anti-neuroblastoma activity.

2018-02-17 | GSE110709 | GEO

Kdm2b promotes cell viability by enhancing DNA damage response in canine hemangiosarcoma

Project description:We found that lysine-specific demethylase 2b (Kdm2b) was highly expressed in HSA cell lines compared to normal canine endothelial cells. Silencing of Kdm2b in HSA cells resulted to increased cell death in vitro by inducing apoptosis through the inactivation of the DNA repair pathways and accumulation of DNA damage. Kdm2b silencing in tumor xenografts results to decreased tumor sizes compared to the control. Treatment of GSK-J4, a histone demethylase inhibitor, also induced apoptosis and cell death. In addition, GSK-J4 treatment decreases tumor sizes. Therefore, we demonstrate that Kdm2b acts as an oncogene in HSA by enhancing the DNA damage response. Moreover, we show that histone demethylase inhibitor GSK-J4 can be used as a therapeutic alternative to doxorubicin for HSA treatment.

2021-02-11 | GSE166540 | GEO

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