Catalytic-independent functions of INTAC confer sensitivity to BET inhibition [RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA1146475 | ENA |
REPOSITORIES: ENA
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Project description:Catalytic-independent functions of INTAC confer sensitivity to BET inhibition
| PRJNA1146470 | ENA
Project description:Catalytic-independent functions of INTAC confer sensitivity to BET inhibition [CUT&Tag]
| PRJNA1146476 | 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 | GSE274475 | GEO
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:Given T-bet is a master regulator for Th1 differentiation that produce IFN-gamma, underlining mechanisms accounted for the distinct GVHD outcomes caused by T-bet- versus IFN-gamma-deficient donor T cells are unclear. We hypothesize that GVHD is regulated by T-bet-dependent but IFN-gamma-independent molecules. To identify these molecules, we isolated donor T cells from spleen cells of the recipients that were transplanted with WT, T-bet-/- or IFN-gamma-/- CD4 T cells for 7 days. The gene profile of isolated T cells was measured by microarray analysis using GeneChip Mouse Genome 430 2.0 arrays (Affymetrix) according to the manufacturerM-^Rs instructions. Array images were analyzed and processed by robust multi-array average (RMA) procedure.
2014-10-30 | E-MTAB-2198 | biostudies-arrayexpress