Ontology highlight
ABSTRACT:
PROVIDER: PRJNA292436 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1723080_1.fastq.gz | Fastqsanger.gz | |||
| SRR1723080_2.fastq.gz | Fastqsanger.gz | |||
| SRR1723090_1.fastq.gz | Fastqsanger.gz | |||
| SRR1723090_2.fastq.gz | Fastqsanger.gz | |||
| SRR1723100_1.fastq.gz | Fastqsanger.gz |
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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. Through the use of CBP/EP300 bromodomain inhibitors (CBP/EP300i), we demonstrate that MYC expression in BETi-resistant cells is dependent on CBP/EP300 bromodomains and that treatment with CBP/EP300i restores phenotypic sensitivity.
2016-01-05 | E-GEOD-64317 | biostudies-arrayexpress
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
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.
2016-01-05 | GSE71909 | GEO
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.
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Project description:Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma (RNA-Seq)
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Project description:Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma (ChIP-Seq)
| PRJNA292437 | ENA
Project description:Silencing of the somatic cell-type specific gene expression programs is a critical yet poorly understood step in nuclear reprogramming. To uncover chromatin-related pathways important for maintaining cell identity, we carried out a reprogramming screen using inhibitors of chromatin factors. Here we identify two independent acetyl-lysine competitive inhibitors targeting the bromodomains of coactivators EP300 and CBP as potent enhancers of reprogramming. EP300/CBP bromodomain inhibition is critical during early stages of reprogramming, significantly accelerates the emergence of iPSCs and, when combined with Dot1L inhibition, enables efficient derivation of human iPSCs with Oct4 and Sox2 alone. In contrast, complete inhibition of catalytic acetyl-transferase activity of EP300/CBP prevents reprogramming. Genome-wide expression analyses indicate that EP300/CBP bromodomain inhibition diminishes the expression of somatic-specific genes without affecting the induction of pluripotency regulators. Through expression analyses, we identify the master mesenchymal transcription factor PRRX1 as a functionally important target in reprogramming that is downregulated upon EP300/CBP bromodomain inhibition. Collectively, our data uncover a role for bromodomain-mediated interactions of EP300/CBP in sustaining cell type specific gene expression programs and maintaining somatic cell identity
2019-02-14 | GSE124582 | GEO
Project description:Silencing of the somatic cell-type specific gene expression programs is a critical yet poorly understood step in nuclear reprogramming. To uncover chromatin-related pathways important for maintaining cell identity, we carried out a reprogramming screen using inhibitors of chromatin factors. Here we identify two independent acetyl-lysine competitive inhibitors targeting the bromodomains of coactivators EP300 and CBP as potent enhancers of reprogramming. EP300/CBP bromodomain inhibition is critical during early stages of reprogramming, significantly accelerates the emergence of iPSCs and, when combined with Dot1L inhibition, enables efficient derivation of human iPSCs with Oct4 and Sox2 alone. In contrast, complete inhibition of catalytic acetyl-transferase activity of EP300/CBP prevents reprogramming. Genome-wide expression analyses indicate that EP300/CBP bromodomain inhibition diminishes the expression of somatic-specific genes without affecting the induction of pluripotency regulators. Through expression analyses, we identify the master mesenchymal transcription factor PRRX1 as a functionally important target in reprogramming that is downregulated upon EP300/CBP bromodomain inhibition. Collectively, our data uncover a role for bromodomain-mediated interactions of EP300/CBP in sustaining cell type specific gene expression programs and maintaining somatic cell identity
2019-02-14 | GSE124581 | GEO
Project description:Silencing of the somatic cell-type specific gene expression programs is a critical yet poorly understood step in nuclear reprogramming. To uncover chromatin-related pathways important for maintaining cell identity, we carried out a reprogramming screen using inhibitors of chromatin factors. Here we identify two independent acetyl-lysine competitive inhibitors targeting the bromodomains of coactivators EP300 and CBP as potent enhancers of reprogramming. EP300/CBP bromodomain inhibition is critical during early stages of reprogramming, significantly accelerates the emergence of iPSCs and, when combined with Dot1L inhibition, enables efficient derivation of human iPSCs with Oct4 and Sox2 alone. In contrast, complete inhibition of catalytic acetyl-transferase activity of EP300/CBP prevents reprogramming. Genome-wide expression analyses indicate that EP300/CBP bromodomain inhibition diminishes the expression of somatic-specific genes without affecting the induction of pluripotency regulators. Through expression analyses, we identify the master mesenchymal transcription factor PRRX1 as a functionally important target in reprogramming that is downregulated upon EP300/CBP bromodomain inhibition. Collectively, our data uncover a role for bromodomain-mediated interactions of EP300/CBP in sustaining cell type specific gene expression programs and maintaining somatic cell identity
2019-02-14 | GSE118218 | GEO
Project description:Multiple myeloma (MM) is a malignancy that is often driven by MYC and that is sustained by IRF4, which are upregulated by super-enhancers. IKZF1 and IKZF3 bind to super-enhancers and can be degraded using immunomodulatory imide drugs (IMiDs). Successful IMiD responses downregulate MYC and IRF4; however, this fails in IMiD-resistant cells. MYC and IRF4 downregulation can also be achieved in IMiD-resistant tumors using inhibitors of BET and EP300 transcriptional coactivator proteins; however, in vivo these drugs have a narrow therapeutic window. By combining IMiDs with EP300 inhibition, we demonstrate greater downregulation of MYC and IRF4, synergistic killing of myeloma in vitro and in vivo, and an increased therapeutic window. Interestingly, this potent combination failed where MYC and IRF4 expression was maintained by high levels of the AP-1 factor BATF. Our results identify an effective drug combination and a previously unrecognized mechanism of IMiD resistance.
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