Gene Expression by RNA-Seq of Peripheral Blood Monocyte with the EZH2 inhibitor GSK-343
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ABSTRACT:
PROVIDER: PRJNA694934 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13532000_1.fastq.gz | Fastqsanger.gz | |||
| SRR13532000_2.fastq.gz | Fastqsanger.gz | |||
| SRR13532001_1.fastq.gz | Fastqsanger.gz | |||
| SRR13532001_2.fastq.gz | Fastqsanger.gz | |||
| SRR13532002_1.fastq.gz | Fastqsanger.gz |
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Project description:Epigenetic regulation of histone H3K27 methylation has recently emerged as a key step during alternative M2-like macrophage (M2) polarization, essential for cardiac repair after Myocardial Infarction (MI). We hypothesized that EZH2, responsible for H3K27 methylation, could act as an epigenetic checkpoint regulator during this process. We demonstrate for the first time inactivation of EZH2 activity, linked to ectopic cytoplasmic localization of the epigenetic enzyme, during monocyte differentiation in vitro as well as in M2 macrophages in vivo during post-MI cardiac inflammation. Moreover, we show that pharmacological EZH2 inhibition, with GSK-343, resolves H3K27 methylation at the promoter of bivalent genes, thus enhancing their expression to promote human monocyte repair functions. In line with this protective effect, GSK-343 treatment accelerated cardiac inflammatory resolution preventing infarct expansion and subsequent cardiac dysfunction after MI in vivo. In conclusion, our study reveals that epigenetic modulation of cardiac-infiltrating immune cells may hold promise to limit adverse cardiac remodeling after MI.
2023-04-24 | GSE165543 | GEO
Project description:The canonical function of EZH2 is methylation of H3K27, although important non-canonical roles have recently been described. EZH2 mutation or deregulated expression has been conclusively demonstrated in the pathogenesis and response to treatment of acute myeloid leukemia (AML), thus making it an attractive therapeutic target. In this study, we therefore investigated whether inhibition of EZH2 might also improve the response of non-APL AML cells to ATRA-based therapy. We focused on GSK-343, a pyridone-containing S-adenosyl-L-methionine (SAM) cofactor-competitive EZH2 inhibitor that is representative of its class, and HKMTI-1-005, a substrate-competitive dual inhibitor targeting EZH2 and the closely related G9A/GLP H3K9 methyltransferases. We found that treatment with HKMTI-1-005 phenocopied EZH2 knockdown and was more effective in inducing myeloid differentiation (both in the absence and presence of ATRA) than GSK-343, despite the efficacy of GSK-343 in terms of abolishing H3K27 trimethylation. Furthermore, transcriptomic analysis revealed that in contrast to treatment with GSK-343, HKMTI-1-005 upregulated the expression of myeloid differentiation pathway genes with and without ATRA, while downregulating genes associated with a hematopoietic stem cell phenotype. Expression data (by HuGene 1.0 ST Affymetrix arrays) from HL-60 AML cells treated for 3 days with EZH2 inhibitors (10µM GSK343 or 2.5µM HKMTI-1-005) with or without AtRA (0.1µM) as well as data from HL-60 cells stabelly transduced with EZH2 KD (shEZH2#1 and shEZH2#2) or control (Scr) lentiviruses, selected and expanded for ~20 days with or without treatment with 0.1µM AtRA for 3 days.
2023-03-10 | GSE222616 | GEO
Project description:Rational: EZH2, an epigenetic enzyme, acts as a transcriptional repressor for genes dysregulated after myocardial infarction (MI). Objective: This study aims to assess the benefits of GSK-343 (EZH2 inhibitor) on cardiac function and lipid metabolism after MI. Methods: Mice were treated daily with vehicle or GSK-343 for 7 days after MI and we evaluated cardiac function (echocardiography), gene expression profiling (RNA-seq) and circulating lipidome (untargeted lipidomics). Results: The 28% MI decreased ejection fraction (EF) was improved by 20% with GSK-343. RNA-seq analysis revealed wide changes in MI normalized with GSK-343: 16 mitochondrial DNA-encoded genes, 57 genes related to mitochondrial function and 15 to lipid metabolism among the 561 down-regulated genes (FC 0.5 and 2; p=10-4). In plasma, while MI enhanced 18 triglycerides (1.24-2.43-fold; p<0.05) and decreased 32 choline glycerophospholipids (PC; 0.55-0.81-fold, p<0.05), GSK-343 normalized these perturbations. In MI, some of these lipids positively correlated with EF (e.g. PC40:6; R=0.84, p=0.004) or with cardiac hypertrophy (e.g. DG18:1_18:2; R=0.81, p=0.007) and GSK-343 abolished most of these correlations. Conclusion: Our study suggests that inhibiting EZH2 is of therapeutic interest to normalize lipid metabolism perturbations and improve cardiac function after MI.
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Project description:Human endothelial colony-forming cells (ECFCs) represent one of the most promising sources of adult stem cells for vascular regeneration after ischemia. Yet, the molecular mechanism underlying the unique properties of these cells to repair damaged blood vessels remains unclear, and new strategies to improve their regenerative function are needed. Here, we demonstrate that ex vivo treatment of ECFCs with a combination of epigenetic drugs (i.e. the histone H3K27 demethylase inhibitor GSK-343 and the histone deacetylase inhibitor panobinostat) improves the migration of these cells and their capacity to form capillary-like networks while also increasing their resistance to serum starvation-induced apoptosis. Furthermore, the kinetic of blood flow recovery is significantly increased upon transplantation of drug-treated ECFCs in a pre-clinical model of hind-limb ischemia. Gene expression profiling by RNA-sequencing reveals that these effects are mediated through the simultaneous activation of several major pro-angiogenic signaling pathways including VEGFR, CXCR4, WNT, NOTCH and SHH. At the molecular level, we provide evidence that the two drugs work through complementary mechanisms that entail the resolving of bivalently marked genes characterized by the presence of both negative (H3K27me3) and positive (H3K4me3 and H3-Ac) histone modifications to create a transcriptionally permissive chromatin environment. Thus, ex vivo treatment with epigenetic drugs increases the vascular repair properties of ECFCs through transient activation of major pro-angiogenic signaling pathways.
2017-09-05 | GSE80819 | GEO
Project description:Human leukemia cell line RS4.11 was treated with GSK-3 inhibitor SB216763 for 20 hours. Gene expression profiling was performed to analyze genes affected by GSK-3 inhibition. Human leukemia cell line RS4.11 was grown in vitro and treated with 10 uM GSK-3 inhibitor SB216763 or solvent DMSO for 20 hours. Total RNA was extracted and microarray analysis was performed. Two controls and three inhibitor treatment samples were analyzed.
2010-05-27 | E-GEOD-19736 | biostudies-arrayexpress
Project description:Analysis of Multiple Myeloma Cell lines JJN-3 and RPMI gene expression following treated with GSK-J4 or Bortezomib Total RNA extracted from cells after 6 or 24 hour treatment with either GSK-J4, GSK-J5, Bortezomib or vehicle
2016-08-21 | E-GEOD-60600 | biostudies-arrayexpress
Project description:Human leukemia cell line RS4.11 was treated with GSK-3 inhibitor SB216763 for 20 hours. Gene expression profiling was performed to analyze genes affected by GSK-3 inhibition.
2010-05-01 | GSE19736 | GEO
Project description:Four glioblastoma cell line U-343 MG, U-343 MGa, U-343 MGa 31L, U-343 MGa Cl2:6 were derived form the same glioblastoma U-343. The RNA-seq was performed to identify their difference and better understand the glioblastoma heterogeneity.
2020-08-10 | E-MTAB-8620 | biostudies-arrayexpress
Project description:Gene expression data from AML cell lines, MOLM-14, U937, THP-1 and HL-60, that were infected with a scrambled control hairpin (shControl), two shRNAs directed against GSK-3B (shGSK3B_1 and shGSK3B_2), or two shRNAs directed against GSK-3A (shGSK3A_5 and shGSK3A_6). Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Long-term survival of patients with AML has changed little over the past decade, necessitating the identification and validation of new AML targets. Integration of genomic approaches with small-molecule and genetic-based high-throughput screening holds the promise of improved discovery of candidate targets for cancer therapy. Here, we identified a role for glycogen synthase kinase 3A (GSK-3A) in AML by performing two independent small-molecule library screens and an shRNA screen for perturbations that induced a differentiation expression signature in AML cells. GSK-3 is a serine-threonine kinase involved in diverse cellular processes including differentiation, signal transduction, cell cycle regulation, and proliferation. We demonstrated that specific loss of GSK-3A induced differentiation in AML by multiple measurements, including induction of gene expression signatures, morphological changes, and cell surface markers consistent with myeloid maturation. GSK-3AM-bM-^@M-^Sspecific suppression also led to impaired growth and proliferation in vitro, induction of apoptosis, loss of colony formation in methylcellulose, and anti-AML activity in vivo. Although the role of GSK-3B has been well studied in cancer development, these studies support a role for GSK-3A in AML. The AML cell lines, MOLM-14, U937, THP-1 and HL-60, were infected with a scrambled control hairpin (shControl), two shRNAs directed against GSK-3B (shGSK3B_1 and shGSK3B_2), and two shRNAs directed against GSK-3A (shGSK3A_5 and shGSK3A_6).
2012-02-27 | E-GEOD-35200 | biostudies-arrayexpress
Project description:Thlaspi arvense 2020-M2-343 Resequencing
| PRJNA1239715 | ENA