Targeting CDK7 function in the RNA Polymerase II transcription cycle in inflammatory arthritis [ChIP-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1074764 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27922905.fastq.gz | Fastqsanger.gz | |||
| SRR27922906.fastq.gz | Fastqsanger.gz | |||
| SRR27922907.fastq.gz | Fastqsanger.gz | |||
| SRR27922908.fastq.gz | Fastqsanger.gz | |||
| SRR27922909.fastq.gz | Fastqsanger.gz |
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Project description:Targeting CDK7 function in the RNA Polymerase II transcription cycle in inflammatory arthritis
| PRJNA1073533 | ENA
Project description:Macrophages are main drivers of inflammation and tissue damage in autoimmune diseases including rheumatoid arthritis1-4. The rate-limiting step for transcription of >70% of inducible genes in macrophages is RNA Polymerase II (Pol II) promoter-proximal pause release5-7, yet, the specific role of Pol II pausing in inflammation or whether it can be modulated therapeutically is unknown. Genetic ablation of a pause-stabilizing negative elongation factor (NELF) in macrophages enhanced the transcriptional response of paused anti-inflammatory genes to LPS, followed by secondary attenuation of inflammatory signaling, and reduced severity of K/BxN-serum transfer (ST) arthritis in mice. To disrupt Pol II pause establishment pharmacologically, we employed covalent inhibitors of the TFIIH-associated cyclin-dependent kinase (CDK) 7, THZ1 and YKL-5-124. Both dramatically reduced Pol II pausing in murine and human macrophages, broadly suppressed induction of pro- but not anti-inflammatory genes, and rapidly reversed pre-established inflammatory macrophage polarization by TNF+IFNγ. In vivo, CDK7i ameliorated the acute K/BxN-ST and chronic progressive hTNF-transgenic arthritis in mice. Finally, CDK7i downregulated a pathogenic gene expression signature in synovial explants from arthritis patients. We propose that interfering with Pol II pausing by targeting CDK7 represents a novel therapeutic opportunity for inflammatory diseases.
2025-01-29 | GSE255108 | GEO
Project description:Macrophages are main drivers of inflammation and tissue damage in autoimmune diseases including rheumatoid arthritis. The rate-limiting step for transcription of >70% of inducible genes in macrophages is RNA Polymerase II (Pol II) promoter-proximal pause release, yet, the specific role of Pol II pausing in inflammation or whether it can be modulated therapeutically is unknown. Genetic ablation of a pause-stabilizing negative elongation factor (NELF) in macrophages enhanced the transcriptional response of paused anti-inflammatory genes to LPS, followed by secondary attenuation of inflammatory signaling, and reduced severity of K/BxN-serum transfer (ST) arthritis in mice. To disrupt Pol II pause establishment pharmacologically, we employed covalent inhibitors of the TFIIH-associated cyclin-dependent kinase (CDK) 7, THZ1 and YKL-5-124. Both dramatically reduced Pol II pausing in murine and human macrophages, broadly suppressed induction of pro- but not anti-inflammatory genes, and rapidly reversed pre-established inflammatory macrophage polarization by TNF+IFNγ. In vivo, CDK7i ameliorated the acute K/BxN-ST and chronic progressive hTNF-transgenic arthritis in mice. Finally, CDK7i downregulated a pathogenic gene expression signature in synovial explants from arthritis patients. We propose that interfering with Pol II pausing by targeting CDK7 represents a novel therapeutic opportunity for inflammatory diseases.
2025-01-29 | GSE255372 | GEO
Project description:Cyclin-dependent kinase 7 (CDK7) plays a critical role in the general regulation of RNA polymerase II-mediated transcription. However, the absence of selective CDK7 inhibitors has hindered the ability to investigate the consequences of acute and prolonged inhibition of CDK7 under normal and pathological conditions. Here we present the discovery and characterization of the first covalent CDK7 inhibitor, CDK7-IN-1, that has the unprecedented ability to target a unique cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7 amongst the 20 known CDKs. Cancer cell line profiling indicates that a subset of cancer cell lines, including T-cell acute lymphoblastic leukemia (T-ALL), exhibit 100-fold greater sensitivity to CDK7-IN-1 over other tumor and normal cell lines. Genome-wide expression analysis in Jurkat T-ALL indicates that CDK7-IN-1 disproportionally affects RUNX1 as well as other components of the TAL1 transcriptional network and its targets, downregulating key regulators of transcription and apoptosis critical for the T-ALL state. These oncogenes are encoded by short-lived mRNA transcripts, are associated with super-enhancers, and exhibit a strong dependency on continuous transcription for sustained expression. Therefore, pharmacological modulation of CDK7 kinase activity may define a method for the identification and treatment of tumor types exhibiting extreme dependencies on transcription for maintenance of the oncogenic state. Jurkat, MM1S, Loucy, and HeLa (WT and Dox-inducible CDK7 mutant) cells were treated with various drugs including a covalent inhibitor of CDK7 (CDK7-IN-1), a reversible inhibitor of CDK7 (CDK7-IN-1), Flavopiridol, Actinomycin D, and DMSO controls. Replicates are annotated.
2014-06-22 | E-GEOD-50624 | biostudies-arrayexpress
Project description:Cyclin-dependent kinase 7 (CDK7) plays a critical role in the general regulation of RNA polymerase II-mediated transcription. However, the absence of selective CDK7 inhibitors has hindered the ability to investigate the consequences of acute and prolonged inhibition of CDK7 under normal and pathological conditions. Here we present the discovery and characterization of the first covalent CDK7 inhibitor, CDK7-IN-1, that has the unprecedented ability to target a unique cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7 amongst the 20 known CDKs. Cancer cell line profiling indicates that a subset of cancer cell lines, including T-cell acute lymphoblastic leukemia (T-ALL), exhibit 100-fold greater sensitivity to CDK7-IN-1 over other tumor and normal cell lines. Genome-wide expression analysis in Jurkat T-ALL indicates that CDK7-IN-1 disproportionally affects RUNX1 as well as other components of the TAL1 transcriptional network and its targets, downregulating key regulators of transcription and apoptosis critical for the T-ALL state. These oncogenes are encoded by short-lived mRNA transcripts, are associated with super-enhancers, and exhibit a strong dependency on continuous transcription for sustained expression. Therefore, pharmacological modulation of CDK7 kinase activity may define a method for the identification and treatment of tumor types exhibiting extreme dependencies on transcription for maintenance of the oncogenic state. Jurkat cells were treated with various drugs including a covalent inhibitor of CDK7 (CDK7-IN-1), a reversible inhibitor of CDK7 (CDK7-IN-1), Flavopiridol, Actinomycin D, and DMSO controls. Replicates are annotated.
2013-12-23 | E-GEOD-50622 | biostudies-arrayexpress
Project description:Cyclin dependent kinases (CDKs) are high value therapeutical targets owing to their important roles in regulating transcription and the cell cycle — two pathways commonly altered in cancer and especially in multiple myeloma (MM). Among CDKs, CDK7 uniquely bridges cell cycle and transcriptional control by activating other cell cycle CDKs and forming the general transcription factor TFIIH. Utilizing a recently developed highly selective covalent inhibitor of CDK7, we demonstrate that CDK7 inhibition elicits a strong therapeutic response in MM blocking proliferation in vitro and driving tumor regression and prolonged survival in vivo. CDK7 inhibition counteracts molecular hallmarks of deregulated cell cycle control at the G1/S checkpoint. Additionally, we show CDK7 inhibition selectively downregulates oncogenic E2F and cell cycle gene expression programs. Combination treatment with JQ1 which target oncogenic enhancer driven gene expression programs proved highly synergistic. These results support CDK7 as an attractive and therapeutically actionable molecular vulnerability in MM. Cell count normalized RNA-seq in Resistant MM cell lines (XG1 and AMO1; 18 total samples; 3 technical replicates) upon treatment with the selective covalent CDK7 inhibitor YKL-5-124 Mariateresa,Fulciniti Nikhil,Munshi
2022-04-01 | GSE172443 | GEO
Project description:Cyclin dependent kinases (CDKs) are high value therapeutical targets owing to their important roles in regulating transcription and the cell cycle — two pathways commonly altered in cancer and especially in multiple myeloma (MM). Among CDKs, CDK7 uniquely bridges cell cycle and transcriptional control by activating other cell cycle CDKs and forming the general transcription factor TFIIH. Utilizing a recently developed highly selective covalent inhibitor of CDK7, we demonstrate that CDK7 inhibition elicits a strong therapeutic response in MM blocking proliferation in vitro and driving tumor regression and prolonged survival in vivo. CDK7 inhibition counteracts molecular hallmarks of deregulated cell cycle control at the G1/S checkpoint. Additionally, we show CDK7 inhibition selectively downregulates oncogenic E2F and cell cycle gene expression programs. Combination treatment with JQ1 which target oncogenic enhancer driven gene expression programs proved highly synergistic. These results support CDK7 as an attractive and therapeutically actionable molecular vulnerability in MM. Cell count normalized RNA-seq in Sensitive MM cell lines (H929 and MM1S; 24 total samples; 3 technical replicates) upon treatment with the selective covalent CDK7 inhibitor YKL-5-124 Mariateresa,Fulciniti Nikhil,Munshi
2022-04-01 | GSE172444 | GEO
Project description:Cyclin dependent kinases (CDKs) are high value therapeutical targets owing to their important roles in regulating transcription and the cell cycle — two pathways commonly altered in cancer and especially in multiple myeloma (MM). Among CDKs, CDK7 uniquely bridges cell cycle and transcriptional control by activating other cell cycle CDKs and forming the general transcription factor TFIIH. Utilizing a recently developed highly selective covalent inhibitor of CDK7, we demonstrate that CDK7 inhibition elicits a strong therapeutic response in MM blocking proliferation in vitro and driving tumor regression and prolonged survival in vivo. CDK7 inhibition counteracts molecular hallmarks of deregulated cell cycle control at the G1/S checkpoint. Additionally, we show CDK7 inhibition selectively downregulates oncogenic E2F and cell cycle gene expression programs. Combination treatment with JQ1 which target oncogenic enhancer driven gene expression programs proved highly synergistic. These results support CDK7 as an attractive and therapeutically actionable molecular vulnerability in MM. Cell count normalized RNA-seq in Resistant MM cell lines (XG1 and AMO1; 18 total samples; 3 technical replicates) upon treatment with the selective covalent CDK7 inhibitor YKL-5-124 Mariateresa,Fulciniti Nikhil,Munshi
2022-04-01 | GSE172442 | GEO
Project description:Cyclin-dependent kinase 7 (CDK7), part of the general transcription factor TFIIH, promotes gene transcription by phosphorylating the C-terminal domain of RNA polymerase II (RNA Pol II). Here, we combine rapid CDK7 kinase inhibition with multi-omics analysis to unravel the direct functions of CDK7 in human cells. CDK7 inhibition causes RNA Pol II retention at promoters, leading to decreased RNA Pol II initiation and immediate global downregulation of transcript synthesis. Elongation, termination, and recruitment of co-transcriptional factors are not directly affected. Although RNA Pol II, initiation factors, and Mediator accumulate at promoters, RNA Pol II complexes can also proceed into gene bodies without promoter-proximal pausing while retaining initiation factors and Mediator. Further downstream, RNA Pol II phosphorylation increases and initiation factors and Mediator are released, allowing recruitment of elongation factors and an increase in RNA Pol II elongation velocity. Collectively, CDK7 kinase activity promotes the release of initiation factors and Mediator from RNA Pol II, facilitating RNA Pol II escape from the promoter.
2024-05-31 | PXD037842 | Pride
Project description:CDK7 regulates RNA polymerase II (RNAPII) initiation, elongation, and termination through incompletely understood mechanisms. Because contaminating kinases precluded CDK7 analysis with nuclear extracts, we completed biochemical assays with purified factors. Reconstitution of RNAPII transcription initiation showed CDK7 inhibition slowed and/or paused RNAPII promoter-proximal transcription, which reduced re-initiation. These CDK7-regulatory functions were Mediator- and TFIID-dependent. Similarly in human cells, CDK7 inhibition reduced transcription by suppressing RNAPII activity at promoters, consistent with reduced initiation and/or re-initiation. Moreover, widespread 3’-end readthrough transcription was observed in CDK7-inhibited cells; mechanistically, this occurred through rapid nuclear depletion of RNAPII elongation and termination factors, including high-confidence CDK7 targets. Collectively, these results define how CDK7 governs RNAPII function at gene 5’-ends and 3’-ends, and reveal that nuclear abundance of elongation and termination factors is kinase-dependent. Because 3’-readthrough transcription is commonly induced during stress, our results further suggest regulated suppression of CDK7 activity may enable this RNAPII transcriptional response.
2025-05-08 | PXD063516 | Pride