IDR-Targeting Compounds Suppress HPV Genome Replication via Disruption of Phospho-BRD4 Association with DNA Damage Response Factors
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE228786 | GEO | 2023/12/15
REPOSITORIES: GEO
Similar Datasets
Project description:Sample name abbreviation is below.
Cell State: Prol for proliferation, Diff for differentiation
Compound (cpd) treatment: DMSO for DMSO-only treatment, 14 or 90 for compound pNPS14 or pNPS90 treatment
BRD4-L IP: L1, L2, and L3 for anti-BRD4-L IP samples 1, 2, and 3
BRD4-S IP: S1, S2, and S3 for anti-BRD4-S IP samples 1, 2, and 3
IgG IP: Ig1, Ig2, and Ig3 for IgG IP samples 1, 2, and 3
Sample ID vs. sample name is listed below.
967246 / Prol_DMSO_L1, 967247 / Prol_DMSO_L2, 967248 / Prol_DMSO_L3
967249 / Prol_14_L1, 967250 / Prol_14_L2, 967251 / Prol_14_L3
967252 / Prol_10_L1, 967253 / Prol_10_L2, 967254 / Prol_10_L3
967255 / Prol_DMSO_S1, 967256 / Prol_DMSO_S2, 967257 / Prol_DMSO_S3
967258 / Prol_14_S1, 967259 / Prol_14_S2, 967260 / Prol_14_S3
967261 / Prol_10_S1, 967262 / Prol_10_S2, 967263 / Prol_10_S3
967264 / Diff_DMSO_L1, 967265 / Diff_DMSO_L2, 967266 / Diff_DMSO_L3
967267 / Diff_14_L1, 967268 / Diff_14_L2, 967269 / Diff_14_L3
967270 / Diff_10_L1, 967271 / Diff_10_L2, 967272 / Diff_10_L3
967273 / Diff_DMSO_S1, 967274 / Diff_DMSO_S2, 967275 / Diff_DMSO_S3
967276 / Diff_14_S1, 967277 / Diff_14_S2, 967278 / Diff_14_S3
967279 / Diff_10_S1, 967280 / Diff_10_S2, 967281 / Diff_10_S3
967282 / Prol_DMSO_Ig1, 967283 / Prol_DMSO_Ig2, 967284 / Prol_DMSO_Ig3
967285 / Diff_DMSO_Ig1, 967286 / Diff_DMSO_Ig2, 967287 / Diff_DMSO_Ig3
2023-03-28 | MSV000091570 | MassIVE
Project description:IDR-Targeting Compounds Suppress HPV Genome Replication via Disruption of Phospho-BRD4 Association with DNA Damage Response Factors
| PRJNA951631 | ENA
Project description:Background: Neurofibromatosis type 2 (NF2) is an autosomal dominant genetic disease characterized by the development of multiple Schwannomas, usually occurring on both VIIIth (vestibular) cranial nerves. Bromodomain and extra-terminal domain (BET) proteins regulate gene transcription and their activity is required in a variety of cancers including malignant peripheral nerve sheath tumors (MPNST). The use of BET inhibitors as a therapeutic option to treat NF2 schwannomas has not been explored and is the focus of this study. Methods: A panel of normal and NF2-null Schwann cell and schwannoma cell lines were used to characterize the impact of the BET inhibitor JQ1 in vitro and in vivo. The mechanism of action was explored by chromatin immunoprecipitation (ChIP) of the BET BRD4, phospho-kinase arrays and immunohistochemistry of BRD4 in human vestibular schwannomas. Results: JQ1 inhibited the proliferation of NF2-null schwannoma and Schwann cell lines in vitro and in vivo. Further, loss of NF2 by CRISPR deletion or siRNA knockdown increased the sensitivity of cells to JQ1. Knock-down experiments identified BRD4 as the BET family member mediating the majority of JQ1 effects on cell proliferation. Immunohistochemistry demonstrated elevated levels of BRD4 protein in human vestibular schwannomas. BRD4 ChIP experiments identified the small G-protein Rac1 and PI3K signaling pathways as sensitive to JQ1. Conclusions: NF2 deficient Schwann cell and schwannoma cells are sensitive to BET inhibition, primarily mediated by BRD4, which is overexpressed in human vestibular schwannomas. BRD4 regulates Rac/Ras and PI3K signaling pathways and inhibition of these pathways by JQ1 impedes NF2 Schwannoma growth. These findings implicate BET inhibition as a therapeutic option for NF2-deficient schwannomas.
2022-08-02 | GSE167560 | GEO
Project description:Inhibition of Brd4 with Jq1 in neurons with or without BDNF stimulation Examination of the effects of Jq1 treatment on primary mouse cortical neurons
2015-08-24 | E-GEOD-63809 | biostudies-arrayexpress
Project description:BRD4 Inhibition of spindle cell malignant peripheral nerve sheath tumor (sMPNST) tumor cells Cells were treated with Brd4 shRNA (3 days) or 500 nM JQ1 (2 days) before RNA isolation
2013-09-13 | E-GEOD-50865 | biostudies-arrayexpress
Project description:The BET (bromodomain and extra terminal) protein family members including BRD4 bind to acetylated lysines on histones and regulate the expression of important oncogenes, e.g., MYC and BCL2. Here we demonstrate the sensitizing effects of the histone hyperacetylation inducing pan-histone deacetylase inhibitor (HDI) panobinostat (PS) on human AML blast progenitor cells (BPCs) to the BET protein inhibitor JQ1. Treatment with JQ1 but not its inactive enantiomer (R-JQ1) was highly lethal against AML BPCs expressing mutant NPM1c+ with or without co-expression of FLT3-ITD, or AML expressing MLL fusion oncoprotein. JQ1 treatment reduced binding of BRD4 and RNA polymerase II to the DNA of MYC and BCL2, and reduced their levels in the AML cells. Co-treatment with JQ1 and the HDAC inhibitor panobinostat (PS) synergistically induced apoptosis of the AML BPCs, but not of normal CD34+ hematopoietic progenitor cells. This was associated with greater attenuation of MYC and BCL2, while increasing p21, BIM and cleaved PARP levels in the AML BPCs. Co-treatment with JQ1 and PS significantly improved the survival of the NOD/SCID mice engrafted with OCI-AML3 or MOLM13 cells (p < 0.01). These findings highlight co-treatment with a BRD4 antagonist and an HDI as a potentially efficacious therapy of AML. Two samples were analyzed (untreated cells, cells treated with JQ1)
2014-01-01 | E-GEOD-51950 | biostudies-arrayexpress
Project description:Transcriptional elongation by RNA polymerase II (Pol II) is regulated by positive transcription elongation factor b (P-TEFb) in association with Bromodomain-containing protein 4 (BRD4). We used genome-wide chromatin immunoprecipitation sequencing in primary human CD4+ T cells to reveal that BRD4 co-localizes with Ser2-phosphorylated Pol II (Pol II Ser2) at both enhancers and promoters of active genes. Disruption of bromodomain:histone acetylation interactions by JQ1, a small-molecule bromodomain inhibitor, resulted in decreased BRD4 binding, reduced Pol II Ser2, and reduced expression of lineage-specific genes in primary human CD4+ T cells. A large number of JQ1-disrupted BRD4 binding regions exhibited di-acetylated H4 (lysine-5 and -8) and H3K27 acetylation (H3K27ac), which correlated with the presence of histone acetyltransferases and deacetylases. Genes associated with BRD4/H3K27ac co-occupancy exhibited significantly higher activity than those associated with H3K27ac or BRD4 binding alone. Comparison of BRD4 binding in T cells and in human embryonic stem cells revealed that enhancer BRD4 binding sites were predominantly lineage-specific. Our findings suggest that BRD4-driven Pol II phosphorylation at serine 2 plays an important role in regulating lineage-specific gene transcription in human CD4+ T cells. Examination of BRD4, total Pol II, serine 2 phosphorylated Pol II and serine 5 phosphorylated Pol II binding in CD4+ T cells (with and without JQ1 treatment) and BRD4 binding in human embryonic stems cell; PolyA RNA expression in CD4+ T cells( with and without JQ1 treatment) using RNA-seq
2012-11-14 | E-GEOD-33281 | biostudies-arrayexpress
Project description:We analyzed anti-proliferative dominant-negative Brd4 mutants that compete with the function of distinct Brd4 domains. We used these Brd4 mutants to compare the Brd4-specific transcriptome with the transcriptome of JQ1 treated cells.
2017-06-09 | GSE92456 | GEO
Project description:BRD4 is amplified and/or up-regiulated in a subset of ovarian cancer which correlates with a poor survival siRNA sensitization screens in the presence of CHK1 inhibitor, LY2606368, identify BRD4 as a therapeutic target in ovarian cancer. BRD4 suppression by either siRNA or using JQ1 increases CBX5 expression
2016-05-01 | GSE78704 | GEO
Project description:Epigenetic pathways regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. While chromatin alterations are, in principle, reversible and often amendable to drug intervention, the promise of targeting such pathways therapeutically has been hampered by our limited understanding of cancer-specific epigenetic dependencies. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukemia (AML) – an aggressive hematopoietic malignancy often associated with aberrant chromatin states. By screening a custom shRNA library targeting known chromatin regulators in a genetically defined AML mouse model, we identify the bromodomain-containing protein Brd4 as a critical requirement for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust anti-leukemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation. Extensive evaluation of JQ1-sensitivity in primary human leukemia samples and in established cell lines revealed a broad activity of this compound against diverse AML subtypes. These effects are, at least in part, due to a requirement for Brd4 in maintaining Myc expression and promoting aberrant self-renewal. Together, our results indicate that Brd4 is a promising therapeutic target in AML and identify a small molecule that efficiently targets Myc. These findings also highlight the utility of RNAi screening as a discovery platform for revealing epigenetic vulnerabilities for direct pharmacologic intervention in cancer. In order to understand downstream targets of Brd4, we performed array in murine or human MLL-AF9/NrasG12D cell line under the condition that Brd4 was suppressed by using shRNAs or the small molecule inhibitor JQ1. To test the hypothesis that Myc might be an important target of Brd4, we performed arrary on murine ectopic Myc overexpression MLL-AF9/NrasG12D cell under JQ1 treatment.
2011-08-03 | E-GEOD-29799 | biostudies-arrayexpress