Transcriptome of NK-92 cells with pharmacological inhibition of SUPT16H, a subunit of FACT complex, by using its inhibitor curaxin 137 (CBL0137)
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA766418 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16077471_1.fastq.gz | Fastqsanger.gz | |||
| SRR16077471_2.fastq.gz | Fastqsanger.gz | |||
| SRR16077472_1.fastq.gz | Fastqsanger.gz | |||
| SRR16077472_2.fastq.gz | Fastqsanger.gz | |||
| SRR16077473_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: This study aims to evaluate the effect of FACT complex inhibitor CBL0137 to the total transcriptome of NK-92 cells through RNA-seq assay. Methods: NK-92 cells were treated with CBL0137 (500 nM) or DMSO for 24 h. RNA samples were extracted and submitted to GENEWIZ (South Plainfield, NJ 07080) for quality control and subsequent rRNA removal through polyA selection, followed by the library preparation. Sequencing was carried out on an Illumina HiSeq platform with the configuration of 2 × 150 bp (paired end), and > 20 million reads per sample were achieved. Differential expression of genes was analyzed by DESeq2. Results: R packages, pheatmap and clusterProfiler, were used for heatmap construction and pathway analysis, respectively. 917 genes were enriched based on the fold-change > 1.5 as well as the adjusted P-value < 0.05. GO biological process (BP) analysis shows that inteferon signaling and anti-viral responses are among top enriched pathways. Expression of interferons and interferon-stimulated genes (ISGs) are increased based on heatmap, which was further validated through quantitative reverse transcription PCR (RT-qPCR) assay. Conclusions: CBL0137 causes the systemic upregulation of IFNs and ISGs with statistical significance in NK-92 cells, which shows the potential of CBL0137 to trigger the anti-viral innate immunity. In addition, due to the upragulation of IFN-gamma pathways, CBL0137 also shows the ability to increase the NK cytotoxicity.
2022-07-29 | GSE184784 | GEO
Project description:CBL0137 is chromatin destabilizing agent, which causing trapping of FACT histone chaperone in chromatin (Gasparian et all, Science TM, 2011, Safina et all, NAR, 2017). We compared effect of CBL0137 on gene expression in mouse organs, expressing FACT (testes, spleen ) or not (lung, liver) to figure out what effects of CBL0137 is due to the inhibition of FACT and which are independent of FACT.
2017-08-18 | GSE102769 | GEO
Project description:EWS/ETS fusion transcription factors, most commonly EWSR1-FLI1, drive initiation and progression of Ewing sarcoma (EwS), a highly aggressive childhood cancer of bone and soft tissues. Even though direct targeting EWSR1-FLI1 is a formidable challenge, epigenetic or transcriptional modulators have been recently proved to be promising therapeutic targets for indirectly disrupting its expression and/or function. Here, we performed transcriptome and functional genomics dataset analyses, and combined with small molecule screening of EwS lines to identify novel epigenetic/transcriptional-targeted therapeutic strategies. SSRP1 and SUPT16H, two subunits of the Facilitates Chromatin Transcription (FACT) complex, are both found to be EWSR1-FLI1-induced essential oncogenes in EwS. The FACT-targeted drug CBL0137 exhibits potent therapeutic efficacy against multiple EwS preclinical models in vitro and in vivo. Mechanistically, the FACT complex and EWS-FLI1 form oncogenic positive feedback loop via mutual transcriptional regulation and activation, and cooperatively promote cell cycle/DNA replication process and IGF1R-PI3K-AKT-mTOR pathway to drive EwS oncogenesis. The FACT inhibitor drug CBL0137 effectively targets the EWSR1-FLI1-FACT circuit, resulting in transcriptional disruption of EWS-FLI1, SSRP1 and their downstream effector oncogenic signatures. Our study illustrates a crucial role of the FACT complex in facilitating the expression and function of EWSR1-FLI1 and demonstrates FACT inhibition as a novel therapeutic strategy against EwS via indirect targeting the oncogenic fusion TF, providing preclinical support for adding EwS to CBL0137’s future clinical trials.
2022-12-31 | GSE195802 | GEO
Project description:EWS/ETS fusion transcription factors, most commonly EWSR1-FLI1, drive initiation and progression of Ewing sarcoma (EwS), a highly aggressive childhood cancer of bone and soft tissues. Even though direct targeting EWSR1-FLI1 is a formidable challenge, epigenetic or transcriptional modulators have been recently proved to be promising therapeutic targets for indirectly disrupting its expression and/or function. Here, we performed transcriptome and functional genomics dataset analyses, and combined with small molecule screening of EwS lines to identify novel epigenetic/transcriptional-targeted therapeutic strategies. SSRP1 and SUPT16H, two subunits of the Facilitates Chromatin Transcription (FACT) complex, are both found to be EWSR1-FLI1-induced essential oncogenes in EwS. The FACT-targeted drug CBL0137 exhibits potent therapeutic efficacy against multiple EwS preclinical models in vitro and in vivo. Mechanistically, the FACT complex and EWS-FLI1 form oncogenic positive feedback loop via mutual transcriptional regulation and activation, and cooperatively promote cell cycle/DNA replication process and IGF1R-PI3K-AKT-mTOR pathway to drive EwS oncogenesis. The FACT inhibitor drug CBL0137 effectively targets the EWSR1-FLI1-FACT circuit, resulting in transcriptional disruption of EWS-FLI1, SSRP1 and their downstream effector oncogenic signatures. Our study illustrates a crucial role of the FACT complex in facilitating the expression and function of EWSR1-FLI1 and demonstrates FACT inhibition as a novel therapeutic strategy against EwS via indirect targeting the oncogenic fusion TF, providing preclinical support for adding EwS to CBL0137’s future clinical trials.
2022-12-31 | GSE195804 | GEO
Project description:EWS/ETS fusion transcription factors, most commonly EWSR1-FLI1, drive initiation and progression of Ewing sarcoma (EwS), a highly aggressive childhood cancer of bone and soft tissues. Even though direct targeting EWSR1-FLI1 is a formidable challenge, epigenetic or transcriptional modulators have been recently proved to be promising therapeutic targets for indirectly disrupting its expression and/or function. Here, we performed transcriptome and functional genomics dataset analyses, and combined with small molecule screening of EwS lines to identify novel epigenetic/transcriptional-targeted therapeutic strategies. SSRP1 and SUPT16H, two subunits of the Facilitates Chromatin Transcription (FACT) complex, are both found to be EWSR1-FLI1-induced essential oncogenes in EwS. The FACT-targeted drug CBL0137 exhibits potent therapeutic efficacy against multiple EwS preclinical models in vitro and in vivo. Mechanistically, the FACT complex and EWS-FLI1 form oncogenic positive feedback loop via mutual transcriptional regulation and activation, and cooperatively promote cell cycle/DNA replication process and IGF1R-PI3K-AKT-mTOR pathway to drive EwS oncogenesis. The FACT inhibitor drug CBL0137 effectively targets the EWSR1-FLI1-FACT circuit, resulting in transcriptional disruption of EWS-FLI1, SSRP1 and their downstream effector oncogenic signatures. Our study illustrates a crucial role of the FACT complex in facilitating the expression and function of EWSR1-FLI1 and demonstrates FACT inhibition as a novel therapeutic strategy against EwS via indirect targeting the oncogenic fusion TF, providing preclinical support for adding EwS to CBL0137’s future clinical trials.
2022-12-31 | GSE195803 | GEO
Project description:Haematopoietic stem cells (HSCs) have long been the focus of developmental and regenerative studies, yet our understanding of the signalling events regulating their specification remains incomplete. We demonstrate that supt16h, a component of the FAcilitates Chromatin Transcription (FACT) complex, is required for HSC formation. Zebrafish supt16h mutants express reduced levels of Notch signalling components, genes essential for HSC development, due to abrogated transcription. Classically, Supt16h regulates transcription and nucleosome reorganization. Whereas global chromatin accessibility in supt16h mutants is unaffected, we observe a specific increase in accessibility at the p53 locus, causing an accumulation of p53 mRNA and protein. We further demonstrate that P53 levels directly influence expression of the Polycomb Group protein, phc1, which functions as a transcriptional repressor of Notch genes. Suppression of phc1 or its upstream regulator, p53, rescues both loss of Notch and loss of HSC phenotypes in supt16h mutants. Taken together, our results highlight a previously uncharacterized relationship between supt16h, p53, and phc1 to specify HSCs via modulation of Notch signalling.
2020-09-01 | GSE127555 | GEO
Project description:Hematopoietic stem cells (HSCs) have long been the focus of developmental and regenerative studies, yet our understanding of the signaling events regulating their specification remains incomplete. We demonstrate that supt16h, a component of the FAcilitates Chromatin Transcription (FACT) complex, is required for HSC formation. Zebrafish supt16h mutants express reduced levels of Notch signaling components, genes essential for HSC development, due to abrogated transcription. Classically, Supt16h regulates transcription and nucleosome reorganization. Whereas global chromatin accessibility in supt16h mutants is unaffected, we observe a specific increase in accessibility at the p53 locus, causing an accumulation of p53 mRNA and protein. We further demonstrate that P53 levels directly influence expression of the Polycomb Group protein, phc1, which functions as a transcriptional repressor of Notch genes. Suppression of phc1 or its upstream regulator, p53, rescues both loss of Notch and loss of HSC phenotypes in supt16h mutants. Taken together, our results highlight a previously uncharacterized relationship between supt16h, p53, and phc1 to specify HSCs via modulation of Notch signaling.
2020-09-01 | GSE116088 | GEO
Project description:Chromatin organization and accessibility are fundamental to how genes are transcriptionally controlled. We identify the first vertebrate mutant for supt16h, a component of the FACT (FAcilitates Chromatin Transcription) complex along with Ssrp1 known to reorganize nucleosomes and assist in transcriptional elongation. We demonstrate its importance in hematopoietic stem cell (HSC) specification by regulating the elongation of Notch genes. Unexpectedly, Assay for Transposase Accessible Chromatin (ATAC) sequencing revealed that loss of supt16h does not affect histone accessibility on a Notch-specific or global level. Although the majority of genes are unaffected, loss of supt16h alters chromatin accessibility significantly at the p53 locus, leading to its overexpression in mutants. Upon downregulation of p53, both loss of Notch and loss of HSC phenotypes are rescued. Notably, ssrp1 mutants possessed normal elongation of Notch genes, levels of P53, and specification of HSCs. Our results highlight the discrete effects of Supt16h and Ssrp1 during HSC specification. Additionally, we demonstrate the relationship between supt16h and p53 during transcriptional elongation to specify HSC fate via modulation of Notch signaling.
2020-09-01 | GSE106341 | GEO
Project description:Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. A high throughput drug screen of 3600 pharmaceutical compounds found that anti-malarials, including quinacrine had potent activity against DIPG neurospheres. CBL0137 is a novel anti-cancer compound developed from quinacrine, which targets Facilitates Chromatin Transcription (FACT), a chromatin remodelling complex involved in transcription, replication, and DNA repair. We have found that CBL0137 displays profound cytotoxic activity against a panel of patient derived DIPG cultures, inhibiting cell proliferation and clonogenic potential, restoring tumor suppressor TP53 and Rb activity and inducing cell death through induction of apoptosis. Moreover, in an orthotopic model of DIPG, treatment with CBL0137 significantly extended animal survival. Histone mutations leading to the loss of histone trimethylation result in epigenetic dysregulation driving DIPG tumorigenesis. Treatment with CBL0137 targets this epigenetic defect, restoring both histone H3.3 acetylation and trimethylation and leading to tumor cell death. Combined epigenetic treatment with the histone deacetylase (HDAC) inhibitor panobinostat led to inhibition of the Rb/E2F1 pathway, and increased the enzymatic activity of enhancer of zeste homolog 2 (EZH2), leading to the restoration of H3K27 trimethylation. This combination therapy had synergistic activity against DIPG neurospheres with induction of apoptosis. Consistent with the in vitro results, the combination of CBL0137 and panobinostat significantly prolonged the survival of mice bearing DIPG orthografts suggesting a potential treatment strategy for DIPG.
2021-03-07 | GSE153883 | GEO
Project description:Chromatin organization and accessibility are fundamental to how genes are transcriptionally controlled. We identify the first vertebrate mutant for supt16h, a component of the FACT (FAcilitates Chromatin Transcription) complex along with Ssrp1 known to reorganize nucleosomes and assist in transcriptional elongation. We demonstrate its importance in hematopoietic stem cell (HSC) specification by regulating the elongation of Notch genes. Unexpectedly, Assay for Transposase Accessible Chromatin (ATAC) sequencing revealed that loss of supt16h does not affect histone accessibility on a Notch-specific or global level. Although the majority of genes are unaffected, loss of supt16h alters chromatin accessibility significantly at the p53 locus, leading to its overexpression in mutants. Upon downregulation of p53, both loss of Notch and loss of HSC phenotypes are rescued. Notably, ssrp1 mutants possessed normal elongation of Notch genes, levels of P53, and specification of HSCs. Our results highlight the discrete effects of Supt16h and Ssrp1 during HSC specification. Additionally, we demonstrate the relationship between supt16h and p53 during transcriptional elongation to specify HSC fate via modulation of Notch signaling.
2020-09-01 | GSE106342 | GEO