Chromatin changes upon short Hsp90 depletion and Sba1 ChIP-Seq
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ABSTRACT:
PROVIDER: PRJNA349007 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR4429105.fastq.gz | Fastqsanger.gz | |||
| SRR4429106.fastq.gz | Fastqsanger.gz | |||
| SRR4429107.fastq.gz | Fastqsanger.gz | |||
| SRR4429108.fastq.gz | Fastqsanger.gz |
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Project description:We report the application of DNase-Seq (adapted from Hesselberth et al., 2009, as described in Zelin et al., 2012) to study the chromatin changes upon short Hsp90 depletion by exploiting temperature-sensitive allele G170D (Nathan and Lindquist, 1995). By generating ~43.6 million reads for wild type and 68.6 million reads for mutant, we were able to reconstitute the hypersensitivity maps under the regular conditions and under the conditions where Hsp90 was heat-inactivated. We find that there is a global reduction of open chromatin upon Hsp90 inactivation, as displayed by the decrease of total DHS size and the DHSs numbers. We also find that loss of Hsp90 leads to the increase of open chromatin at certain locations associated with chromatin remodelers such as RSC. Overall this study shows that short term improper functioning of Hsp90 results in genome-wide chromatin perturbations thereby demonstrating an Hsp90-dependence of chromatin architecture.
2016-11-03 | GSE88875 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2016-11-03 | GSE88877 | GEO
Project description:Hsp90 is a molecular chaperone involved in the regulation and maturation of kinases and transcription factors. In Caenorhabditis elegans, it contributes to the development of fertility, maintenance of muscle structure, the regulation of heat-shock response and dauer state. To understand the consequences of Hsp90-depletion, we studied Hsp90 RNAi-treated nematodes by DNA microarrays and mass spectrometry. We find that upon development of phenotypes the levels of chaperones and Hsp90 cofactors are increased, while specific proteins related to the innate immune response are depleted. In microarrays, we further find many differentially expressed genes related to gonad and larval development. These genes form an expression cluster that is regulated independently from the immune response implying separate pathways of Hsp90-involvement. Using fluorescent reporter strains for the differentially expressed immune response genes skr-5, dod-24 and clec-60 we observe that their activity in intestinal tissues is influenced by Hsp90-depletion. Instead, effects on the development are evident in both gonad arms. After Hsp90-depletion, changes can be observed in early embryos and adults containing fluorescence-tagged versions of SEPA-1, CAV-1 or PUD-1, all of which are downregulated after Hsp90-depletion. Our observations identify molecular events for Hsp90-RNAi induced phenotypes during development and immune responses, which may help to separately investigate independent Hsp90-influenced processes that are relevant during the nematode’s life and development. We used microarrays to detail the global programme of gene expression after RNAi-mediated Hsp90 knock-down.
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Project description:aThese experiments address the effects of depleting Hsp90 upon the transcriptome of the major fungal pathogen, Candida albicans, during the heat shock response. The data show that key virulence factors are regulated in response to heat shock, and that Hsp90 exerts major effects on the heat shock transcriptome.a
2016-05-16 | E-MTAB-4075 | biostudies-arrayexpress
Project description:We report the application of DHS-Seq and digital genomic footprinting to study chromatin changes and transcription factor-DNA binding upon long-term Hsp90 depletion utilizing the temperature-sensitive allele G170D. By generating about 86 and 85.6 million reads for wild type and mutant, we were able to reconstitute the chromatin accessibility and the transcription factor-DNA binding maps under regular conditions and under conditions where Hsp90 was long-term inactivated. We find that there is a global reduction of transcription factor binding sites with concurrent loss of open chromatin upon Hsp90 inactivation. This data was used in conjunction with our previous work involving DHS-Seq studies and short-term Hsp90 depletion (GEO GSE88875) to distinguish the affected transcription factor networks and the chromatin changes upon short- and long-term Hsp90 depletion. We identified two different modes of Hsp90 operation on transcription factor activities – short-term inactivation of Hsp90 altered transcription factor DNA binding activities, whereas long-term Hsp90 inactivation affected the steady-state levels of transcription factors. Overall, this study shows that Hsp90 regulates multiple transcription factor protein families and modulates chromatin architecture on a genome-wide scale.
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Project description:Purpose: Characterization of transcriptomic alterations upon HPS90 inhibition in human LN229 and T98G glioblastoma cells in vitro. Methods: LN229 and T98G glioblastoma cells were treated with 10 nM of the HSP90 inhibitor NW457 or the vehicle control for 24 h, and total RNA was subjected to 3' RNA sequencing. Results: Distinct transcriptomic alterations were observed, dominated by a transcriptional upregulation of the heat shock response. Conclusion: HSP90 inhibition resulted in distinct transcriptomic alterations and a clear upregulation of the heat shock response.
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Project description:Inhibition of the HSP90 chaperone results in depletion of many signaling proteins that drive tumorigenesis, such as downstream effectors of KRAS, the most commonly mutated human oncogene. As a consequence, several small-molecule HSP90 inhibitors are being evaluated in clinical trials as anticancer agents. To prospectively identify mechanisms through which HSP90-dependent cancer cells evade pharmacologic HSP90 blockade, we generated multiple mutant KRAS-driven cancer cell lines with acquired resistance to the purine-scaffold HSP90 inhibitor PU-H71. All cell lines retained dependence on HSP90 function, as evidenced by sensitivity to short hairpin RNA-mediated suppression of HSP90AA1 or HSP90AB1 (also called HSP90α and HSP90β, respectively), and exhibited two types of genomic alterations that interfere with the effects of PU-H71 on cell viability and proliferation: (i) a Y142N missense mutation in the ATP-binding domain of HSP90α that co-occurred with amplification of the HSP90AA1 locus, (ii) genomic amplification and overexpression of the ABCB1 gene encoding the MDR1 drug efflux pump. In support of a functional role for these alterations, exogenous expression of HSP90α Y142N conferred PU-H71 resistance to HSP90-dependent cells, and pharmacologic MDR1 inhibition with tariquidar or lowering ABCB1 expression restored sensitivity to PU-H71 in ABCB1-amplified cells. Finally, comparison with structurally distinct HSP90 inhibitors currently in clinical development revealed that PU-H71 resistance could be overcome, in part, by ganetespib (also known as STA9090) but not tanespimycin (also known as 17-AAG). Together, these data identify potential mechanisms of acquired resistance to small molecules targeting HSP90 that may warrant proactive screening for additional HSP90 inhibitors or rational combination therapies.
2016-12-31 | GSE85733 | GEO
Project description:Inhibition of the HSP90 chaperone results in depletion of many signaling proteins that drive tumorigenesis, such as downstream effectors of KRAS, the most commonly mutated human oncogene. As a consequence, several small-molecule HSP90 inhibitors are being evaluated in clinical trials as anticancer agents. To prospectively identify mechanisms through which HSP90-dependent cancer cells evade pharmacologic HSP90 blockade, we generated multiple mutant KRAS-driven cancer cell lines with acquired resistance to the purine-scaffold HSP90 inhibitor PU-H71. All cell lines retained dependence on HSP90 function, as evidenced by sensitivity to short hairpin RNA-mediated suppression of HSP90AA1 or HSP90AB1 (also called HSP90α and HSP90β, respectively), and exhibited two types of genomic alterations that interfere with the effects of PU-H71 on cell viability and proliferation: (i) a Y142N missense mutation in the ATP-binding domain of HSP90α that co-occurred with amplification of the HSP90AA1 locus, (ii) genomic amplification and overexpression of the ABCB1 gene encoding the MDR1 drug efflux pump. In support of a functional role for these alterations, exogenous expression of HSP90α Y142N conferred PU-H71 resistance to HSP90-dependent cells, and pharmacologic MDR1 inhibition with tariquidar or lowering ABCB1 expression restored sensitivity to PU-H71 in ABCB1-amplified cells. Finally, comparison with structurally distinct HSP90 inhibitors currently in clinical development revealed that PU-H71 resistance could be overcome, in part, by ganetespib (also known as STA9090) but not tanespimycin (also known as 17-AAG). Together, these data identify potential mechanisms of acquired resistance to small molecules targeting HSP90 that may warrant proactive screening for additional HSP90 inhibitors or rational combination therapies.
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