Catalytic-independent functions of INTAC confer sensitivity to BET inhibition [CUT&Tag]
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ABSTRACT:
PROVIDER: PRJNA1146476 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30193110_1.fastq.gz | Fastqsanger.gz | |||
| SRR30193110_2.fastq.gz | Fastqsanger.gz | |||
| SRR30193111_1.fastq.gz | Fastqsanger.gz | |||
| SRR30193111_2.fastq.gz | Fastqsanger.gz | |||
| SRR30193112_1.fastq.gz | Fastqsanger.gz |
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Project description:Catalytic-independent functions of INTAC confer sensitivity to BET inhibition
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Project description:Chromatin and transcription regulators are critical to defining cell identity through shaping epigenetic and transcriptional landscapes, with their misregulation being closely linked to oncogenesis. Pharmacologically targeting these regulators, particularly the transcription activating BET proteins, has emerged as a promising approach in cancer therapy, yet intrinsic or acquired resistance frequently occurs with poorly understood mechanisms. Using genome-wide CRISPR screens, we find that BET inhibitor efficacy in mediating transcriptional silencing and growth inhibition depends on the auxiliary module of the INTAC complex, a global regulator of polymerase pause-release dynamics. This process bypasses a requirement for INTAC's catalytic activities and instead leverages direct engagement of the auxiliary module with the RACK7/ZMYND8–KDM5C complex to remove histone H3K4 methylation. Targeted degradation of the COMPASS subunit WDR5 to attenuate H3K4 methylation restores sensitivity to BET inhibitors, highlighting how simultaneously targeting coordinated chromatin and transcription regulators can circumvent drug-resistant tumors.
2024-10-11 | GSE274475 | GEO
Project description:Catalytic-independent functions of INTAC confer sensitivity to BET inhibition [RNA-seq]
| PRJNA1146475 | ENA
Project description:Chromatin and transcription regulators are critical to defining cell identity through shaping epigenetic and transcriptional landscapes, with their misregulation being closely linked to oncogenesis. Pharmacologically targeting these regulators, particularly the transcription activating BET proteins, has emerged as a promising approach in cancer therapy, yet intrinsic or acquired resistance frequently occurs with poorly understood mechanisms. Using genome-wide CRISPR screens, we find that BET inhibitor efficacy in mediating transcriptional silencing and growth inhibition depends on the auxiliary module of the INTAC complex, a global regulator of polymerase pause-release dynamics. This process bypasses a requirement for INTAC's catalytic activities and instead leverages direct engagement of the auxiliary module with the RACK7/ZMYND8–KDM5C complex to remove histone H3K4 methylation. Targeted degradation of the COMPASS subunit WDR5 to attenuate H3K4 methylation restores sensitivity to BET inhibitors, highlighting how simultaneously targeting coordinated chromatin and transcription regulators can circumvent drug-resistant tumors.
2024-10-11 | GSE274473 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-10-11 | GSE274476 | GEO
Project description:Gene expression in metazoans is controlled by promoter-proximal pausing of RNA polymerase II, which can undergo productive elongation or early termination. Integrator-PP2A (INTAC) plays a crucial role in determining the fate of paused polymerases, but the underlying mechanisms remain unclear. Here we establish a rapid degradation system to dissect the direct functions of INTAC RNA endonuclease and phosphatase modules. We find that both catalytic modules function at most if not all active promoters and enhancers, yet differentially affect polymerase fate. The endonuclease module induces early termination, with its disruption leading to accumulation of non-competent polymerases and downregulation of highly expressed genes, while competent polymerases accumulate at lowly expressed genes and non- coding elements, leading to their upregulation. The phosphatase module primarily prevents the release of paused polymerases and limits transcriptional activation, especially for highly paused genes. Thus both INTAC’s catalytic modules have unexpectedly general yet distinct roles in dynamic transcriptional control. We performed PRO-seq, ChIP-seq, or TT-seq to investigate the role of INTAC in regulating transcription.
2023-04-19 | GSE223264 | GEO
Project description:Gene expression in metazoans is controlled by promoter-proximal pausing of RNA polymerase II, which can undergo productive elongation or early termination. Integrator-PP2A (INTAC) plays a crucial role in determining the fate of paused polymerases, but the underlying mechanisms remain unclear. Here we establish a rapid degradation system to dissect the direct functions of INTAC RNA endonuclease and phosphatase modules. We find that both catalytic modules function at most if not all active promoters and enhancers, yet differentially affect polymerase fate. The endonuclease module induces early termination, with its disruption leading to accumulation of non-competent polymerases and downregulation of highly expressed genes, while competent polymerases accumulate at lowly expressed genes and non- coding elements, leading to their upregulation. The phosphatase module primarily prevents the release of paused polymerases and limits transcriptional activation, especially for highly paused genes. Thus both INTAC’s catalytic modules have unexpectedly general yet distinct roles in dynamic transcriptional control. We performed PRO-seq, ChIP-seq, or TT-seq to investigate the role of INTAC in regulating transcription.
2023-04-19 | GSE223260 | GEO
Project description:Gene expression in metazoans is controlled by promoter-proximal pausing of RNA polymerase II, which can undergo productive elongation or early termination. Integrator-PP2A (INTAC) plays a crucial role in determining the fate of paused polymerases, but the underlying mechanisms remain unclear. Here we establish a rapid degradation system to dissect the direct functions of INTAC RNA endonuclease and phosphatase modules. We find that both catalytic modules function at most if not all active promoters and enhancers, yet differentially affect polymerase fate. The endonuclease module induces early termination, with its disruption leading to accumulation of non-competent polymerases and downregulation of highly expressed genes, while competent polymerases accumulate at lowly expressed genes and non- coding elements, leading to their upregulation. The phosphatase module primarily prevents the release of paused polymerases and limits transcriptional activation, especially for highly paused genes. Thus both INTAC’s catalytic modules have unexpectedly general yet distinct roles in dynamic transcriptional control. We performed PRO-seq, ChIP-seq, or TT-seq to investigate the role of INTAC in regulating transcription.
2023-04-19 | GSE223252 | GEO
Project description:Gene expression in metazoans is controlled by promoter-proximal pausing of RNA polymerase II, which can undergo productive elongation or early termination. Integrator-PP2A (INTAC) plays a crucial role in determining the fate of paused polymerases, but the underlying mechanisms remain unclear. Here we establish a rapid degradation system to dissect the direct functions of INTAC RNA endonuclease and phosphatase modules. We find that both catalytic modules function at most if not all active promoters and enhancers, yet differentially affect polymerase fate. The endonuclease module induces early termination, with its disruption leading to accumulation of non-competent polymerases and downregulation of highly expressed genes, while competent polymerases accumulate at lowly expressed genes and non- coding elements, leading to their upregulation. The phosphatase module primarily prevents the release of paused polymerases and limits transcriptional activation, especially for highly paused genes. Thus both INTAC’s catalytic modules have unexpectedly general yet distinct roles in dynamic transcriptional control. This SuperSeries is composed of the SubSeries listed below.
2023-04-19 | GSE223265 | GEO
Project description:Cyclin-dependent kinase 12 (CDK12) interacts with Cyclin K to form a a functional nuclear kinase complex, which has been reported to phosphorylate the carboxyl-terminal domain (CTD) of RNA polymerase II (Pol II) for transcriptional regulation and co-transcriptional RNA processing. However, the precise mechanisms and targets of CDK12 action remain largely unknown. Here, we combined a chemical genetic screen and phosphoproteomic strategies and identified a landscape of nuclear CDK12 substrates, which included proteins that regulate transcription, chromatin organization, and RNA splicing. Next, we confirmed that the LEO1 subunit of the transcription elongation factor PAF1 complex (PAF1C) is a bona fide substrate of CDK12. Acute depletion of LEO1 reduces Pol II occupancy on the chromatin, while mutations of LEO1 phosphorylation sites to non-phosphorylatable alanine residues attenuated the association of PAF1C with elongating Pol II and chromatin, resulting in impaired processive transcription elongation. Furthermore, LEO1 C-terminus could interact with and be dephosphorylated by the Integrator-PP2A complex (INTAC), while acute depletion of INTAC in cells promotes the association between PAF1C and elongating Pol II on the chromatin. Together, this study provides a novel transcriptional regulatory mechanism that the CDK12-INTAC axis fine-tunes LEO1 phosphorylation for processive transcription elongation.
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