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

ABSTRACT: 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).

ORGANISM(S): Mus musculus

PROVIDER: GSE49886 | GEO | 2016/03/11

SECONDARY ACCESSION(S): PRJNA215243

REPOSITORIES: GEO

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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

KDM6 histone demethylase inhibitor GSK-J4 induces metal and stress responses in multiple myeloma cells [GSK-J4]

Project description:Thioneins are cysteine-rich, evolutionary conserved apoproteins that regulate divalent metal homeostasis by virtue of their metal-chelation properties resulting in the ligand-bound metallothionein state. Previous studies have demonstrated a transient upregulation (102- 103-fold) of a cluster of metallothionein genes as part of a transcriptional response to a class of histone demethylase tool compounds targeting human Fe2+ dependent ketoglutarate oxygenases KDM6A (UTX) and KDM6B (JmjD3). Exposure of multiple myeloma cells to the prototypic bioactive KDM6 inhibitor GSK-J4 induces apoptotic cell death and transcriptomic profiles that are dominated by metal and metabolic stress response signatures. We here investigate the hypothesis that the metal-chelating property of GSK-J4 provides the means for transport and intracellular release of Zn2+ leading to a metallothionein transcriptomic response signature. Live cell imaging upon myeloma cell exposure to GSK-J4 shows a transient increase of intracellular free Zn2+ concentrations upon KDM6 inhibitor treatment consistent with a model of inhibitor mediated metal transport. Comparison of KDM6 inhibitor and ZnSO4 treatments in the presence or absence of metal chelators show that both treatment conditions induce different transcription factor repertoires with an overlapping MTF1 transcriptional regulation responsible for metallothionein and metal ion transport regulation.

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KDM6 histone demethylase inhibitor GSK-J4 induces metal and stress responses in multiple myeloma cells [ZNSO]

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KDM6 histone demethylase inhibitor GSK-J4 induces metal and stress responses in multiple myeloma cells [GSK-J4]

Project description:KDM6 histone demethylase inhibitor GSK-J4 induces metal and stress responses in multiple myeloma cells [GSK-J4]

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Activation of the Integrated Stress Response by a Jumonji Histone Demethylase Inhibitor Induces Pro-Apoptotic Metabolic Reprogramming in Multiple Myeloma

Project description:Regulation of gene expression by chromatin modification through methylation of histone lysine residues is a dynamic, reversible process that when deregulated is associated with cancer development. In multiple myeloma, combined inhibition of the histone demethylases JARID1B, UTX and JmjD3 by the small molecule GSK-J4 prevents cellular glutamine utilization leading to amino acids deprivation, activates the integrated stress response via GCN2-dependent ATF4 activation, and induces apoptosis. This response is associated with a profound upregulation of metallothionein genes. Combined with clinical data demonstrating that overexpression of JARID1B is associated with shorter survival in multiple myeloma patients, this study highlights histone demethylases as epigenetic drug targets and places this demethylase inhibitor chemotype as having unique potential relative to established anti-myeloma treatment options. In total there are 7 different samples analyzed and one input control. Treatments are carried out with the demethylase inhibitor (or DMSO as negative control) at 6h and 48h, or with LNA targeting demethylases (or scrambled LNA) at 7 days. A negative control at 0h is included.

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

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2017-08-31 | GSE89817 | 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.

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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.

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

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