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EZH2 inhibitor efficacy in non-Hodgkin lymphoma does not require suppression of H3K27 mono-methylation [ChIP-Seq]

ABSTRACT: Here we report the discovery of highly potent and selective EZH2 small molecule inhibitors, their validation by a cellular thermal shift assay, their application across a large lymphoma cell panel and their efficacy in GCBDLBCL xenograft models. Baseline ChIP-seq measurement of KARPAS-422 cell line H3K27me3 levels, without treatment. Two samples -- H3K27me3 and Input included as control.

ORGANISM(S): Homo sapiens

SUBMITTER: Barbara Bryant

PROVIDER: E-GEOD-62057 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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EZH2 inhibitor efficacy in non-Hodgkin's lymphoma does not require suppression of H3K27 monomethylation.

Bradley William D WD Arora Shilpi S Busby Jennifer J Balasubramanian Srividya S Gehling Victor S VS Nasveschuk Christopher G CG Vaswani Rishi G RG Yuan Chih-Chi CC Hatton Charlie C Zhao Feng F Williamson Kaylyn E KE Iyer Priyadarshini P Méndez Jacqui J Campbell Robert R Cantone Nico N Garapaty-Rao Shivani S Audia James E JE Cook Andrew S AS Dakin Les A LA Albrecht Brian K BK Harmange Jean-Christophe JC Daniels Danette L DL Cummings Richard T RT Bryant Barbara M BM Normant Emmanuel E Trojer Patrick P

Chemistry & biology 20141101 11

The histone lysine methyltransferase (MT) Enhancer of Zeste Homolog 2 (EZH2) is considered an oncogenic driver in a subset of germinal center B-cell-like diffuse large B cell lymphoma (GCB-DLBCL) and follicular lymphoma due to the presence of recurrent, monoallelic mutations in the EZH2 catalytic domain. These genomic data suggest that targeting the EZH2 MT activity is a valid therapeutic strategy for the treatment of lymphoma patients with EZH2 mutations. Here we report the identification of hi ...[more]

PMID: 25457180

Similar Datasets

EZH2 inhibitor efficacy in non-Hodgkin lymphoma does not require suppression of H3K27 mono-methylation [RNA-Seq]

Project description:Here we report the discovery of highly potent and selective EZH2 small molecule inhibitors, their validation by a cellular thermal shift assay, their application across a large lymphoma cell panel and their efficacy in GCBDLBCL xenograft models. RNA-seq of KARPAS-422 cell line RNA, in duplicate, treated with DMSO as control, and EZH2 inhibitors CPI360, EPZ-6438 and GSK126. Eight samples in total.

2015-04-13 | E-GEOD-62056 | biostudies-arrayexpress

Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma (ChIP-Seq)

Project description:Pharmacological inhibition of chromatin co-regulatory factors represents a clinically validated strategy to modulate oncogenic signaling through selective attenuation of gene expression. Here, we demonstrate that CBP/EP300 bromodomain inhibition preferentially abrogates the viability of multiple myeloma cell lines. Phenotypic effects are preceded by the direct transcriptional suppression of the lymphocyte-specific transcription factor IRF4 and the subsequent down-regulation of the IRF4 transcriptional program. Ectopic expression of IRF4 antagonizes the phenotypic effects of CBP/EP300 bromodomain inhibition and prevents the suppression of the IRF4 target c-MYC. These findings suggest that CBP/EP300 bromodomain inhibition represents a viable therapeutic strategy for targeting multiple myeloma and other lymphoid malignancies dependent on the IRF4 network. A total of 13 ChIP-seq samples were sequenced. Samples were treated with control (DMSO) or test compound (2.5 uM SGC-CBP30 or 0.25uM CPI267203) for 6 hours. Signal from input samples was included to subtract background signal from each ChIP-seq sample. Antibodies used were against p300, H3K18ac, H3K27ac, or BRD4.

2016-01-05 | E-GEOD-71909 | biostudies-arrayexpress

Inhibitors of the histone lysine demethylase KDM1A are broadly efficacious in AML by evicting the enzyme from chromatin [ChIP-Seq]

Project description:Examine the distribution of KDM1A and the histone H3K4me2 mark on chromatin following treatment with two distinct classes of KDM1A inhibitors - an irreversible inhibitor (RN-1) and a reversible inhibitor (GSK690) 15 samples total from two treated cell lines - 9 from Kasumi-1 and 6 from SKNO-1. Controls included were input DNA isolated from the treated cells.

2016-02-10 | E-GEOD-71739 | biostudies-arrayexpress

DNase IM-bM-^@M-^Shypersensitive exons colocalize with promoters and distal regulatory elements

Project description:Native-ChIP was performed to determine whether cross-linked ChIP-Seq enrichments observed at DHS exons result from co-precipitation with proximal promoter. Native ChIP-Seq was performed on H3K4me3 and H3K27me3 histone modifications in human cells

2013-06-01 | E-GEOD-46945 | biostudies-arrayexpress

Non-canonical PRC1.1 targets active genes independent of H3K27me3 and is essential for leukemogenesis

Project description:Polycomb proteins are classical regulators of stem cell self-renewal and cell lineage commitment and are frequently deregulated in cancer. Here we find that the non-canonical PRC1.1 complex, as identified by mass spectrometry-based proteomics, is critically important for human leukemic stem cells. Downmodulation of PRC1.1 complex members, like the DNA-binding subunit KDM2B, strongly reduces cell proliferation in vitro and delays or even abrogates leukemogenesis in vivo in humanized xenograft models. PRC1.1 components are significantly overexpressed in primary AML CD34+ cells. Besides a set of genes that is co-targeted by PRC1 and PRC2, ChIP-seq studies show that PRC1.1 also binds a distinct set of genes that are devoid of H3K27me3 suggesting a gene regulatory role independent of PRC2. This set encompasses genes involved in metabolism, which have transcriptionally active chromatin profiles. These data indicate that PRC1.1 controls distinct gene clusters involved in unique cell biological processes required for leukemic cell viability. K562 cells were transduced with lentiviral GFP-fusion vectors encoding GFP-CBX2, PCGF1-GPF, PCGF2-GFP, PCGF4-GFP, GFP-RING1A or GFP-RING1B. K562 cells expressing GFP-fusions at relatively low levels were sorted and expanded and subsequently crosslinked. ChIP reactions were performed using the following antibodies: anti-GFP (ab290, Abcam), anti-H3K27me3 (07-449, Millipore), anti-H3K4me3 (ab8580, Abcam), anti-H2AK119ub (D27C4, Cell Signaling Technology), and anti-KDM2B (ab137547, Abcam). Furthermore, ChIP reactions were performed using primary AML CD34+ and Peripheral Blood (PB) CD34+ cells using anti-H3K27me3 (07-449, Millipore), anti-H3K4me3 (ab8580, Abcam), anti-H2AK119ub (D27C4, Cell Signaling Technology), anti-KDM2B (ab137547, Abcam).

2015-11-24 | E-GEOD-54580 | biostudies-arrayexpress

Genome-wide maps of Yan chromatin association

Project description:High-resolution genome-wide binding of Yan used to confirm the presence of high-density regions seen in ChIP-chip ChIP-Seq of Yan protein in stage 11 Drosophila embryos

2013-03-01 | E-GEOD-34040 | biostudies-arrayexpress

Genome-wide profiling of trimethylated histone H3 lysine 27 (H3K27me3) in wide-type, brm, clf, and brm clf mutant seedlings

Project description:By using ChIP-seq, we found that loss of BRM activity in developing seedlings leads to ectopic and increased H3K27me3 deposition at several hundred genes, indicating the critical role of BRM in preventing the inappropriate deposition of this histone mark. Removal of CLF in brm mutant could partcially suppress the increased H3K27me3. Examination of H3K27me3 in 14-day-old wt, brm, clf, and brm clf seedlings. Two biological replicates for each one.

2015-03-09 | E-GEOD-53620 | biostudies-arrayexpress

H3K27me3 is maintained at a reduced level in Suz12(Bgal/Bgal) ESCs [RNA-Seq]

Project description:Suz12(Bgal/Bgal) ESCs express a truncated form of Suz12 fused to Beta-galactosidase. These cells maintain a reduced level of H3K27me3 despite this mutation to a core component of PRC2, unlike Eed-/- ESCs whose H3K27me3 is ablated. RNA-seq was performed in wild type and Suz12(Bgal/Bgal) ESCs, here used to demonstrate the coverage of the Suz12 gene in mRNA reads.

2013-07-22 | E-GEOD-47484 | biostudies-arrayexpress

H3K27me3 is maintained at a reduced level in Suz12(Bgal/Bgal) ESCs [ChIP-Seq]

Project description:Suz12(Bgal/Bgal) ESCs express a truncated form of Suz12 fused to Beta-galactosidase. These cells maintain a reduced level of H3K27me3 despite this mutation to a core component of PRC2, unlike Eed-/- ESCs whose H3K27me3 is ablated. Two ESC lines mutant in genes of core components of Polycomb Repressive Complex 2 were assessed for H3K27me3 by ChIP-seq, as compared to a wild type ESC line.

2013-07-22 | E-GEOD-47483 | biostudies-arrayexpress

PRC2 coordinates lineage fidelity and DNA methylation during ESC differentiation (ChIP-Seq)

Project description:Polycomb Repressive Complex 2 (PRC2) catalyzes histone H3 lysine 27 tri-methylation, an epigenetic modification associated with gene repression. H3K27me3 is enriched at the promoters of a large cohort of developmental genes in embryonic stem cells (ESCs). Loss of H3K27me3 leads to a failure of ESCs to properly differentiate, which presents a major roadblock for dissecting the precise roles of PRC2 activity during lineage commitment. While recent studies suggest that loss of H3K27me3 leads to changes in DNA methylation in ESCs, how these two pathways coordinate to regulate gene expression programs during lineage commitment is poorly understood. Here, we analyzed gene expression and DNA methylation levels in several PRC2 mutant ESC lines that maintain varying levels of H3K27me3. We found that maintenance of intermediate levels of H3K27me3 allowed for proper temporal activation of lineage genes during directed differentiation of ESCs to spinal motor neurons (SMNs). However, genes that function to specify other lineages failed to be repressed, suggesting that PRC2 activity is necessary for lineage fidelity. We also found that H3K27me3 is antagonistic to DNA methylation in cis. Furthermore, loss of H3K27me3 leads to a gain in promoter DNA methylation in developmental genes in ESCs and in lineage genes during differentiation. Thus, our data suggest a role for PRC2 in coordinating dynamic gene repression while protecting against inappropriate promoter DNA methylation during differentiation. Embryonic Stem Cell (ESC) lines mutant for PRC2 core components Suz12 (Suz12GT and Suz12delta) and Eed (Eednull) were subjected to in vitro directed differentiation down the spinal motor neuron lineage. ESCs and day 5 differentiated cells from the three mutant lines and wild-type were used for H3K27me3 ChIP-seq.

2014-11-17 | E-GEOD-53505 | biostudies-arrayexpress

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