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Super Elongation Complex (SEC) and global genomic analyses in murine embryonic stem (ES) cells and in human cells in response to activation signals.

ABSTRACT: 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.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE30267 | GEO | 2011/07/19

SECONDARY ACCESSION(S): PRJNA155129

REPOSITORIES: GEO

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Super Elongation Complex (SEC) and global genomic analyses in murine embryonic stem (ES) cells and in human cells in response to activation signals.

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

Knockdown of Brd4 or SEC affects the HMBA-induced global Pol II pausing release

Project description:To test whether Brd4 and SEC co-regulate the release of promoter-proximally paused Pol II, we performed Pol II ChIP-Seq to analyze the effect of depletion of Brd4 or SEC on HMBA-induced pause release in HCT116 cells.

2019-01-12 | GSE76784 | GEO

Schizosaccharomyces pombe Pol II Transcription Elongation Factor ELL Functions as Part of a Rudimentary Super Elongation Complex

Project description:ELL family transcription factors activate the overall rate of RNA polymerase II (Pol II) transcription elongation by binding directly to Pol II and suppressing its tendency to pause. In metazoa, ELL regulates Pol II transcription elongation as part of a large multisubunit complex referred to as the Super Elongation Complex (SEC), which includes P-TEFb and EAF, AF9 or ENL, and an AFF family protein. Although orthologs of ELL and EAF have been identified in lower eukaryotes including S. pombe, it has been unclear whether SEC-like complexes function in lower eukaryotes. In this report, we describe isolation from S. pombe of an ELL-containing complex with features of a rudimentary SEC. This complex includes S. pombe Ell1, Eaf1, and a previously uncharacterized protein we designate Ell1 binding protein 1 (Ebp1), which is distantly related to metazoan AFF family members. Like the metazoan SEC, this S. pombe ELL complex appears to function broadly in Pol II transcription. Interestingly, it appears to have a particularly important role in regulating genes involved in cell separation.

2018-07-26 | GSE115636 | GEO

The little elongation complex (LEC) regulates small nuclear RNA transcription

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

Gene expression Microarray analysis for HEK293 WT and ELL KD with control and 1hr EGF stimulated conditions.

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

PAF1, a molecular regulator of promoter-proximal pausing by RNA Polymerase II

Project description:The control of promoter-proximal pausing and the release of RNA polymerase II (RNA Pol II) is a widely used mechanism for regulating gene expression in metazoans, especially for genes that respond to environmental and developmental cues. Here, we identify Pol II associated Factor 1 (PAF1) as a major regulator of promoter-proximal pausing. Knockdown of PAF1 leads to increased release of paused Pol II into gene bodies at thousands of genes. Genes with the highest levels of paused Pol II exhibit the largest redistribution of Pol II from the promoter-proximal region into the gene body in the absence of PAF1. PAF1 depletion results in increased nascent transcription and increased levels of phosphorylation of Pol II’s c-terminal domain on serine 2 (Ser2P). These changes can be explained by the recruitment of the Ser2P kinase Super Elongation Complex (SEC) effecting increased release of paused Pol II into productive elongation, thus establishing a novel function for PAF1 as a major regulator of pausing in metazoans. ChIP-seq of Pol II of different forms, SEC subunits, PAFc subunits and H2Bub in human cell lines targeted by PAF1 or scramble shRNA. ChIP-seq of total Pol II in HCT116 cells targeted by BRE1A or scramble shRNA. ChIP-seq of total Pol II in S2 cells targeted by Paf1 or LacZ RNAi. Total RNA-seq, nascent RNA-seq and GRO-seq in HCT116 cells targeted by PAF1 or scramble shRNA.

2015-08-13 | E-GEOD-70408 | biostudies-arrayexpress

Gene expression Microarray analysis for HEK293 WT and ELL KD with control and 1hr EGF stimulated conditions.

2011-12-09 | E-GEOD-34104 | biostudies-arrayexpress

PAF1, a molecular regulator of promoter-proximal pausing by RNA Polymerase II

2015-08-13 | GSE70408 | GEO

The little elongation complex (LEC) regulates small nuclear RNA transcription

2011-12-22 | GSE32120 | GEO

Targeting Processive Transcription Elongation via SEC Disruption for MYC-Induced Cancer Therapy

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

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