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Targeting of SMARCA4 bromodomain selectively inhibits leukemic cell proliferation

ABSTRACT: Targeting of SMARCA4 bromodomain selectively inhibits leukemic cell proliferation

PROVIDER: PRJNA281224 | ENA |

REPOSITORIES: ENA

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Targeting of SMARCA4 bromodomain selectively inhibits leukemic cell proliferation

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-07-12 | E-GEOD-67924 | biostudies-arrayexpress

Targeting of SMARCA4 bromodomain selectively inhibits leukemic cell proliferation

Project description:This SuperSeries is composed of the SubSeries listed below.

2015-07-12 | GSE67924 | GEO

Gene expression changes in MV4-11 cells upon SMARCA4 knock-down and PFI-3 treatment

Project description:Pharmacological inhibition of the SMARCA4 bromodomain inhibited human leukemic cell proliferation, phenocopying SMARCA4 knockdown in these cells. We performed microarray analysis of global gene expression changes in MV4-11 cells after 6 days of PFI-3 treatment and after SMARCA4 knock-down. With this analysis we identified several genes whose expression was similarly up- or down-regulated upon inhibitor treatment and SMARCA4 depletion. Human acute monocytic leukemia cells (MV4-11, ACC 102) were lentivirally transduced with shRNA taregting SMARCA4 (KD) or with a negative control shRNA (Scr). In a parallel experiment MV4-11 cells were treated for 6 days with 10 uM PFI-3, which is SMARCA4, SMARCA2 and PBRM1 bromodomain inhibitor, or DMSO as a negative control. All sample types were prepared in triplicates.

2015-07-12 | E-GEOD-67920 | biostudies-arrayexpress

Gene expression changes in MV4-11 cells upon SMARCA4 knock-down and PFI-3 treatment

2015-07-12 | GSE67920 | GEO

Gene expression profiling on isogenic lines expressing wild-type and mutant forms of SMARCA2 and SMARCA4

Project description:SMARCA2 and SMARCA4 are two mutually exclusive ATPase subunits of SWI/SNF complex. SMARCA4 deficient lung cancer population selectively depend on SMARCA2 for cancer growth phenotype. Rescue experiments with ectopic expression of wild-type, bromodomain mutant and ATPase dead SMARCA2 and SMARCA4 highlight that ATPase domain is the drug target. In this study, we performed genome-wide microarray and differential gene expression profiling on isogenic lung cancer lines expressing cDNA rescue constructs for wild-type, bromodomain mutant and ATPase dead SMARCA2 and SMARCA4

2015-07-21 | GSE69088 | GEO

SMARCA4/2 loss inhibits chemotherapy-induced apoptosis by restricting IP3R3-mediated Ca2+ flux to mitochondria

Project description:Inactivating mutations in SMARCA4 and concurrent epigenetic silencing of SMARCA2 characterize subsets of ovarian and lung cancers. Concomitant loss of these key subunits of SWI/SNF chromatin remodeling complexes in both cancers is associated with chemotherapy resistance and poor prognosis. Here, we discover that SMARCA4/2 loss inhibits chemotherapy-induced apoptosis through disrupting intracellular organelle calcium ion (Ca2+) release in these cancers. By restricting chromatin accessibility to ITPR3, encoding Ca2+ channel IP3R3, SMARCA4/2 deficiency causes reduced IP3R3 expression leading to impaired Ca2+ transfer from the endoplasmic reticulum to mitochondria required for apoptosis induction. Reactivation of SMARCA2 by a histone deacetylase inhibitor rescues IP3R3 expression and enhances cisplatin response in SMARCA4/2-deficient cancer cells both in vitro and in vivo. Our findings elucidate the contribution of SMARCA4/2 to Ca2+-dependent apoptosis induction, which may be exploited to enhance chemotherapy response in SMARCA4/2-deficient cancers.

| EGAS00001005448 | EGA

Disrupting mitochondrial copper distribution inhibits leukemic stem cell self-renewal

Project description:Disrupting mitochondrial copper distribution inhibits leukemic stem cell self-renewal

| PRJNA609914 | ENA

Comparison of gene expression changes in AML cells after SMARCA4, SMARCD2 or DPF2 knock-down

Project description:We explored the role of SMARCA4 and the two Brahma associated factors SMARCD2 and DPF2 in leukaemia. We observed the selective requirement for these factors for leukemic cell expansion, as well as extended survival of mice transplanted with leukaemic cells with reduced expression of these genes. Gene expression profiling revealed largely similar alterations with the down-regulation of each of these three factors, suggesting a concerted function in transformed blood cells. These changes included loss of pluripotency-associated signature but did not correlate with c-MYC down-regulation. Human acute monocytic leukemia cells (THP-1, ACC 16) were lentivirally transduced with pLKO-puro vectors carrying shRNAs against SMARCA4, SMARCD2 or DPF2. As a negative control, THP-1 cells were transduced with pLKO-puro-shScr (Scrambled). All samples were prepared as biological triplicates.

2015-07-12 | E-GEOD-67923 | biostudies-arrayexpress

Leukemic cell lines expression profile of OTX015 compared to JQ1 and DMSO controls

Project description:Gene signature determination of the effect of a new bromodomain inhibitor among a representative set of leukemic cell lines OTX015 vs. DMSO and JQ1 vs. DMSO

2015-06-25 | E-GEOD-70263 | biostudies-arrayexpress

SMARCA4 regulates gene expression and higher-order chromatin structure in proliferating mammary epithelial cells

Project description:The packaging of DNA into chromatin plays an important role in transcriptional regulation and nuclear processes. Brahma related gene-1 SMARCA4 (also known as BRG1), the essential ATPase subunit of the mammalian SWI/SNF chromatin remodeling complex, uses the energy from ATP hydrolysis to disrupt nucleosomes at target regions. Although the transcriptional role of SMARCA4 at gene promoters is well-studied, less is known about its role in higher-order genome organization. SMARCA4 knockdown in human mammary epithelial MCF-10A cells resulted in 176 up-regulated genes, including many related to lipid and calcium metabolism, and 1292 down-regulated genes, some of which encode extracellular matrix (ECM) components that can exert mechanical forces and affect nuclear structure. ChIP-seq analysis of SMARCA4 localization and SMARCA4-bound super-enhancers demonstrated extensive binding at intergenic regions. Furthermore, Hi-C analysis showed extensive SMARCA4-mediated alterations in higher-order genome organization at multiple resolutions. First, SMARCA4 knockdown resulted in clustering of intra- and inter- sub-telomeric regions, demonstrating a novel role for SMARCA4 in telomere organization. SMARCA4 binding was enriched at TAD (Topologically Associating Domain) boundaries, and SMARCA4 knockdown resulted in weakening of TAD boundary strength. Taken together, these findings provide a dynamic view of SMARCA4-dependent changes in higher-order chromatin organization and gene expression, identifying SMARCA4 as a novel component of chromatin organization. Hi-C and RNA-seq experiments were conducted in MCF-10A shSCRAM and shSMARCA4 cells. SMARCA4 ChIP-seq was conducted in wildtype MCF-10A cells.

2016-06-02 | E-GEOD-74716 | biostudies-arrayexpress

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