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VEGF promotes RNAPII pausing release through ETS1 to stimulate angiogenesis

ABSTRACT: RNA polymerase II (RNAPII) pausing release is a recently recognized checkpoint for transcriptional regulation. The biological roles of RNAPII pausing release and the mechanisms that by which extracellular signals control it are incompletely understood. Here we identify a novel mechanism by which VEGF stimulates RNAPII pausing-release through acetylation of ETS1, a master endothelial cell transcriptional regulator. In endothelial cells (ECs), ETS1 uniquely bound transcribed gene promoters and stimulated their expression by broadly increasing RNA polymerase II (RNAPII) pause release. VEGF enhanced ETS1 chromatin occupancy. Furthermore, VEGF increased ETS1 acetylation, enhancing its binding by BRD4 and thereby stimulating RNAPII pause release. This ETS1-mediated transduction of VEGF signaling to increase RNAPII pausing release was essential for EC angiogenic responses in vitro and in vivo. Together, our results define a new angiogenic pathway in which VEGF enhances ETS1-Brd4 interaction to broadly promote RNAPII pause release and drive angiogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE93030 | GEO | 2016/12/31

SECONDARY ACCESSION(S): PRJNA359488

REPOSITORIES: GEO

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Homo sapiens

Project description:VEGF promotes RNAPII pausing release through ETS1 to stimulate angiogenesis

| PRJNA359488 | ENA

Integrator complex regulates NELF-mediated RNA Polymerase II pause/release and processivity at coding genes [RNA-seq]

Project description:RNAPII pausing/termination shortly after initiation is a hallmark of gene regulation. However, the molecular mechanisms involved are still to be uncovered. Here, we show that NELF interacts with Integrator complex subunits (INTScom) forming a stable complex with RNPII and Spt5. The interaction between NELF and INTScom subunits is RNA and DNA independent. Using both HIV-1 promoter and genome wide analyses, we demonstrate that Integrator subunits specifically control NELF-mediated RNAPII pause/release at coding genes. The strength of RNAPII pausing is determined by the nature of the NELF-associated complex. Interestingly, in addition to controlling RNAPII pause release INTS11 catalytic subunit of the INTScom is required for the synthesis of full length mRNA. Finally, INTScom-target genes are enriched in HIV-1 TAR/ NELF-binding element and in a 3’box sequence required for snRNA biogenesis. Revealing these unexpected functions of INTScom in regulating RNAPII pausing/release and completion of mRNA synthesis of NELF-target genes will contribute to our understanding of the gene expression cycle. Genome-wide expression in HeLa cells in the absence of Integrator 11, or NELF or mock (control) depleted by strand-specific RNASeq (Illumina)

2015-05-19 | E-GEOD-60585 | biostudies-arrayexpress

Integrator complex regulates NELF-mediated RNA Polymerase II pause/release and processivity at coding genes [ChIP-seq]

Project description:RNAPII pausing/termination shortly after initiation is a hallmark of gene regulation. However, the molecular mechanisms involved are still to be uncovered. Here, we show that NELF interacts with Integrator complex subunits (INTScom) forming a stable complex with RNPII and Spt5. The interaction between NELF and INTScom subunits is RNA and DNA independent. Using both HIV-1 promoter and genome wide analyses, we demonstrate that Integrator subunits specifically control NELF-mediated RNAPII pause/release at coding genes. The strength of RNAPII pausing is determined by the nature of the NELF-associated complex. Interestingly, in addition to controlling RNAPII pause release INTS11 catalytic subunit of the INTScom is required for the synthesis of full length mRNA. Finally, INTScom-target genes are enriched in HIV-1 TAR/ NELF-binding element and in a 3’box sequence required for snRNA biogenesis. Revealing these unexpected functions of INTScom in regulating RNAPII pausing/release and completion of mRNA synthesis of NELF-target genes will contribute to our understanding of the gene expression cycle. Binding profiles of Integrator subunits in HeLa cells by ChIP-Seq (Illumina) Please note that the MACS14*.tar.gz contains MACS output bed and xls files and the 'readme.txt' contains a detailed description of each file.

2015-05-19 | E-GEOD-60584 | biostudies-arrayexpress

MYC enhancer invasion promotes prognostic cancer type-specific gene programs through an epigenetic switch

Project description:The transcription factor MYC is overexpressed in most cancers, where it drives multiple hallmarks of cancer progression. MYC is known to promote oncogenic transcription by binding to active promoters. In addition, MYC has also been shown to invade distal enhancers when expressed at oncogenic levels, but this enhancer binding has been proposed to have low gene-regulatory potential. Here, we demonstrate that MYC enhancer binding directly promotes cancer type-specific gene programs predictive of poor patient prognosis. MYC induces transcription of enhancer RNA through recruitment of RNAPII, rather than regulating RNAPII pause-release as is the case at promoters. This is mediated by MYC-induced H3K9 demethylation by KDM3A and acetylation by GCN5, leading to enhancer-specific BRD4 recruitment through its bromodomains, which facilitates RNAPII recruitment. Thus, we propose that MYC drives prognostic cancer type-specific gene programs by promoting RNAPII recruitment to enhancers through induction of an epigenetic switch.

2023-11-30 | PXD039586 | Pride

Integrator complex regulates NELF-mediated RNA Polymerase II pause/release and processivity at coding genes [ChIP-seq]

2015-05-19 | GSE60584 | GEO

Integrator complex regulates NELF-mediated RNA Polymerase II pause/release and processivity at coding genes [RNA-seq]

2015-05-19 | GSE60585 | GEO

A PP2A-Integrator complex fine-tunes transcription by opposing CDK9

Project description:Gene expression by RNA Polymerase II (RNAPII) is tightly controlled by Cyclindependent kinases (CDKs) at discrete checkpoints during the transcription cycle. The RNAPII pausing checkpoint, engaged after transcription initiation, is controlled by CDK9 to regulate transcription in metazoans. We discovered that CDK9-mediated RNAPII pause-release is functionally opposed by a protein phosphatase 2A (PP2A) complex. PP2A dynamically competes for key CDK9 substrates, DSIF and RNAPIICTD, and is recruited to transcription pausing sites by the Integrator complex subunit INTS6. INTS6 depletion confers resistance to CDK9 inhibition in a variety of normal and tumor cell lines. Loss of INTS6 abolishes the Integrator-PP2A association leading to unrestrained CDK9 activity, which amplifies transcriptional responses. Pharmacological PP2A activation synergizes with CDK9 inhibition to kill MLLrearranged leukemias and solid tumors and provide therapeutic benefit in vivo. These data demonstrate that finely-tuned gene expression relies on the balance of kinase and phosphatase activity at the pausing checkpoint.

2022-08-12 | PXD022962 | Pride

Brd4 and JMJD6-associated Anti-pause Enhancers in Regulation of Transcriptional Pause Release

Project description:Distal enhancers characterized by H3K4me1 mark play critical roles in developmental and transcriptional programs. However, potential roles of specific distal regulatory elements in regulating RNA Polymerase II (Pol II) promoter-proximal pause release remain poorly investigated. Here we report that a unique cohort of jumonji C domain-containing protein 6 (JMJD6) and bromodomain-containing protein 4 (Brd4) co-bound distal enhancers, termed anti-pause enhancers (A-PEs), regulate promoter-proximal pause release of a large subset of transcription units via long-range interactions. Brd4-dependent JMJD6 recruitment on A-PEs mediates erasure of H4R3me2(s), which is directly read by 7SK snRNA, and decapping/demethylation of 7SK snRNA, ensuring the dismissal of the 7SKsnRNA/HEXIM inhibitory complex. The interactions of both JMJD6 and Brd4 with the P-TEFb complex permit its activation and pause release of regulated coding genes. The functions of JMJD6/ Brd4-associated dual histone and RNA demethylase activity on anti-pause enhancers have intriguing implications for these proteins in development, homeostasis and disease. All Gro-seq(s) were designed to reveal the transcriptional targets of JMJD6 and Brd4, and assess the role of JMJD6 and Brd4 in Pol II promoter-proximal pause release. All ChIP-seq(s) were designed to understand the unique features, associated molecular mechanisms and functions of the anti-pause enhancers (A-PEs) discovered in the current study.

2014-01-14 | E-GEOD-51633 | biostudies-arrayexpress

BRD4 loading at the transcription start site mediates pause-release and underlies the disproportionate transcriptional response to BET bromodomain inhibition [GRO-Seq]

Project description:BET bromodomain inhibition (BETi) abrogates cancer cell growth by disrupting oncogenic gene expression. BRD4 loading at enhancers has been suggested to mediate pause-release and underlie the selective transcriptional response to BETi. Here, we utilized GRO-seq coupled with ChIP-seq to assess the association between gene control elements and the transcriptional response to BETi. Genes immediately down-regulated by BETi display a marked pause-release defect with a minimal impact on transcript elongation within the gene body. Surprisingly, we find that BRD4 at super-enhancers does not render its associated genes or enhancer RNAs preferentially sensitive to BETi. In contrast, disproportionate loading of BRD4 at transcription start sites (TSS) correlates with the transcriptional response to BETi. Moreover, BRD4 loading at TSSs, but not enhancers, is associated with enhanced promoter-proximal pausing following BETi. Our findings stress a mechanistic role of promoter-associated BRD4 in pause-release and suggest that BRD4 loading at the TSS drives the selective transcriptional response to BETi.

2023-01-06 | GSE70449 | GEO

BRD4 loading at the transcription start site mediates pause-release and underlies the disproportionate transcriptional response to BET bromodomain inhibition [ChIP-Seq]

2023-01-06 | GSE70448 | GEO

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