Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: GSE30268
PROVIDER: PRJNA143729 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR299129.fastq.gz | Fastqsanger.gz | |||
| SRR299130.fastq.gz | Fastqsanger.gz | |||
| SRR299131.fastq.gz | Fastqsanger.gz | |||
| SRR299132.fastq.gz | Fastqsanger.gz | |||
| SRR299133.fastq.gz | Fastqsanger.gz |
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Project description:Transcriptional regulation of developmentally controlled genes is at the heart of differentiation and organogenesis. In this study, we have performed global genomic analyses in murine embryonic stem (ES) cells and in human cells in response to activation signals. We have identified an essential role for the ELL/P-TEFbcontaining Super Elongation Complex (SEC) in the regulation of gene expression including several genes bearing paused RNA polymerase II (Pol II). Paused Pol II has been proposed to be associated with loci that respond rapidly to environmental stimuli. However, our studies in ES cells have also identified a requirement for SEC at genes without preloaded Pol II, which also respond dynamically to differentiation signals. Our findings suggest that SEC is a major class of active P-TEFb-containing complexes required for transcriptional activation in response to environmental cues such as differentiation signals. Examination of ELL2, AFF4, and Pol II before and after activation signals in two cell types.
2011-07-19 | E-GEOD-30267 | biostudies-arrayexpress
Project description:MYCN amplification in neuroblastoma predicts particular poor prognosis and directly targeting of MYCN remains a major challenge. We conducted a targeted screen of transcription elongation factors and identified the super elongation complex (SEC) as a unique vulnerability in MYCN-amplified neuroblastoma. Mechanistically, MYCN directly interacts with the SEC subunit EAF1 and recruits the complex to the target gene loci for ensuing processive transcription elongation, rendering MYCN-mediated transcriptional activation highly dependent on SEC. Pharmacological inhibition of SEC by KL-1 or KL-2 elicits selective cell death in MYCN-overexpressing neuroblastoma cells. Furthermore, drug combination screening identifies the BCL-2 inhibitor ABT-199 synergistic with KL-2. Pre-clinical studies manifest that KL-2 and ABT-199 co-treatment significantly suppresses tumorigenesis and shows therapeutic value in multiple neuroblastoma allograft and xenograft models. These findings highlight SEC as a targetable vulnerability, and simultaneous inhibition of SEC and BCL-2 holds great promise for the treatment of MYCN-driven neuroblastoma.
2023-02-27 | GSE199086 | GEO
Project description:MYCN amplification in neuroblastoma leads to aberrant expression of MYCN oncoprotein, which binds active genes promoting transcriptional amplification. Yet how MYCN coordinates transcription elongation to meet productive transcriptional amplification and which elongation machinery represents MYCN-driven vulnerability remain to be identified. We conducted a targeted screen of transcription elongation factors and identified the super elongation complex (SEC) as a unique vulnerability in MYCN-amplified neuroblastomas. MYCN directly binds EAF1 and recruits SEC to enhance processive transcription elongation. Depletion of EAF1 or AFF1/AFF4, another core subunit of SEC, leads to a global reduction in transcription elongation and elicits selective apoptosis of MYCN-amplified neuroblastoma cells. A combination screen reveals SEC inhibition synergistically potentiates the therapeutic efficacies of FDA-approved BCL2 antagonist ABT-199, in part due to suppression of MCL1 expression, both in MYCN-amplified neuroblastoma cells and in patient-derived xenografts. These findings identify disruption of the MYCN-SEC regulatory axis as a promising therapeutic strategy in neuroblastoma.
2023-05-10 | PXD039332 | Pride
Project description:Transcriptional regulation of developmentally controlled genes is at the heart of differentiation and organogenesis. In this study, we have performed global genomic analyses in murine embryonic stem (ES) cells and in human cells in response to activation signals. We have identified an essential role for the ELL/P-TEFbcontaining Super Elongation Complex (SEC) in the regulation of gene expression including several genes bearing paused RNA polymerase II (Pol II). Paused Pol II has been proposed to be associated with loci that respond rapidly to environmental stimuli. However, our studies in ES cells have also identified a requirement for SEC at genes without preloaded Pol II, which also respond dynamically to differentiation signals. Our findings suggest that SEC is a major class of active P-TEFb-containing complexes required for transcriptional activation in response to environmental cues such as differentiation signals.
2011-07-19 | GSE30267 | GEO
Project description:In this study, using human AF9 as representative of Super Elongation Complex (SEC) components, we have studied detailed mechanisms of functional cross-talk between global transcriptional repression and efficient DNA damage repair during genotoxic stress.As a result of which we have identified interactors of Human AF9.
2024-05-18 | PXD049385 | Pride
Project description:The transcription factor T-bet directs Th1 cell differentiation, but the molecular mechanisms that underlie this lineage-specific gene regulation are not completely understood. Here, we show that T-bet acts through super-enhancers in human and mouse Th1 cells to recruit Mediator and P-TEFb in the form of the super elongation complex (SEC). Th1-specific genes are poised in Th2 cells while T-bet-mediated recruitment of P-TEFb in Th1 cells activates transcriptional elongation. P-TEFb is recruited to both genes and super-enhancers, where it activates enhancer RNA transcription. P-TEFb inhibition and Mediator and SEC knockdown selectively block activation of T-bet target genes and P-TEFb inhibition abrogates Th1-associated experimental autoimmune uveitis. T-bet activity is independent of changes in NF-κB RelA and Brd4 binding, but T-bet- and NF-κB-mediated pathways converge to allow P-TEFb recruitment. These data support a model in which lineage-specifying factors allow recruitment of P-TEFb to poised genes to promote differentiation of alternative T cell fates.
2016-06-08 | GSE62482 | GEO
Project description:The Eleven-nineteen Lysine-rich Leukemia (ELL)-containing Super Elongation Complex (SEC) containing P-TEFb is a key regulator in the expression of HOX genes in Mixed Lineage Leukemia (MLL)-based leukemia. We have identified an SEC-like complex in Drosophila, as well as a distinct ELL-containing complex that lacks P-TEFb and other components of SEC named the "little elongation complex" (LEC). LEC subunits are highly enriched at RNA Polymerase II (Pol II) transcribed small nuclear RNA (snRNA) genes and the loss of LEC results in decreased snRNA expression in both flies and mammals. The discovery of specificity of SEC and LEC complexes for mRNA and snRNA containing genes, respectively, suggest the presence of specific classes of elongation factors for each class of genes transcribed by RNA polymerase II.
2011-12-22 | GSE32120 | GEO
Project description:The Eleven-nineteen Lysine-rich Leukemia (ELL)-containing Super Elongation Complex (SEC) containing P-TEFb is a key regulator in the expression of HOX genes in Mixed Lineage Leukemia (MLL)-based leukemia. We have identified an SEC-like complex in Drosophila, as well as a distinct ELL-containing complex that lacks P-TEFb and other components of SEC named the "little elongation complex" (LEC). LEC subunits are highly enriched at RNA Polymerase II (Pol II) transcribed small nuclear RNA (snRNA) genes and the loss of LEC results in decreased snRNA expression in both flies and mammals. The discovery of specificity of SEC and LEC complexes for mRNA and snRNA containing genes, respectively, suggest the presence of specific classes of elongation factors for each class of genes transcribed by RNA polymerase II. Examination of genome-wide binding profiles for ELL, Ice1, Lilli, and Pol II in D. melanogaster and by ChIP-seq. Identification of differentially expressed genes in ELL-RNAi and Ice1-RNAi in D. melanogaster by RNA-seq. Examination of genome-wide binding profiles for ELL in M. musculus. Identification of differentially expressed genes in ELL-RNAi in M. musculus by RNA-seq.
2011-12-22 | E-GEOD-32120 | biostudies-arrayexpress
Project description:The super elongation complex (SEC) is required for robust and productive transcription through release of RNA polymerase II (Pol II) with its P-TEFb module and promoting transcriptional processivity with its ELL2 subunit. Malfunction of SEC contributes to multiple human diseases including cancer. Here, we identify peptidomimetic lead compounds, KL-1 and its structural homolog KL-2, which disrupt the interaction between the SEC scaffolding protein AFF4 and P-TEFb, resulting in impaired release of Pol II from promoter-proximal pause sites and a reduced average rate of processive transcription elongation. SEC is required for induction of heat-shock genes and treating cells with KL-1 and KL-2 attenuates the heat-shock response from Drosophila to human. SEC inhibition downregulates MYC and MYC-dependent transcriptional programs in mammalian cells and delays tumor progression in a mouse xenograft model of MYC-driven cancer, indicating that small-molecule disruptors of SEC could be used for targeted therapy of MYC-induced cancer.
2018-10-26 | GSE112608 | GEO
Project description:Transcription is a multi-stage process that coordinates several steps within the transcription cycle including chromatin reorganization, RNA polymerase II recruitment, initiation, promoter clearance and elongation. Recent advances have identified the super elongation complex (SEC), containing the eleven nineteen lysine rich leukemia protein (ELL), as a key regulator of transcriptional elongation. We show here that ELL plays a diverse and kinetically distinct role prior to its assembly into the SEC by stabilizing Pol II recruitment/initiation and entry into the pause site. Loss of ELL destabilizes the PIC complexes and results in disruption of early elongation and promoter proximal chromatin structure prior to recruitment of AFF4 and other SEC components. These changes result in significantly reduced transcriptional activation of rapidly induced genes. Thus, ELL plays an early and essential role during rapid high amplitude gene expression that is required for both Pol II pause site entry and release.
2011-12-09 | GSE34104 | GEO