SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA437109 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5806770.fastq.gz | Fastqsanger.gz | |||
| SRR5806780.fastq.gz | Fastqsanger.gz | |||
| SRR5806790.fastq.gz | Fastqsanger.gz | |||
| SRR5806800.fastq.gz | Fastqsanger.gz | |||
| SRR5806810.fastq.gz | Fastqsanger.gz |
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Project description:Defining direct targets of transcription factors and regulatory pathways is key to understanding their role in physiology and disease. Here we combine SLAM-seq, a novel method for direct quantification of newly synthesized mRNAs, with pharmacological and rapid chemical-genetic perturbation to interrogate primary transcriptional targets of BRD4 and MYC and define the response to BET bromodomain inhibitors (BETi). While BRD4 acts as a global co-activator of Pol2-dependent transcription in a BET bromodomain-dependent manner, therapeutic BETi doses deregulate a small set of hypersensitive target genes. In contrast to BRD4, MYC primarily acts as a selective transcriptional activator that controls basic metabolic processes such as ribosome biogenesis and de-novo purine synthesis across diverse cancer contexts. Beyond defining primary regulatory functions of BRD4 and MYC in cancer, our study establishes a simple, robust and scalable approach to dissect direct transcriptional targets of any gene or pathway.
2018-04-05 | GSE100708 | GEO
Project description:Defining direct targets of transcription factors and regulatory pathways is key to understanding their role in physiology and disease. Here we combine SLAM-seq, a novel method for direct quantification of newly synthesized mRNAs, with pharmacological and rapid chemical-genetic perturbation to interrogate primary transcriptional targets of BRD4 and MYC and define the response to BET bromodomain inhibitors (BETi). While BRD4 acts as a global co-activator of Pol2-dependent transcription in a BET bromodomain-dependent manner, therapeutic BETi doses deregulate a small set of hypersensitive target genes. In contrast to BRD4, MYC primarily acts as a selective transcriptional activator that controls basic metabolic processes such as ribosome biogenesis and de-novo purine synthesis across diverse cancer contexts. Beyond defining primary regulatory functions of BRD4 and MYC in cancer, our study establishes a simple, robust and scalable approach to dissect direct transcriptional targets of any gene or pathway.
2018-04-05 | GSE111460 | GEO
Project description:Defining direct targets of transcription factors and regulatory pathways is key to understanding their role in physiology and disease. Here we combine SLAM-seq, a novel method for direct quantification of newly synthesized mRNAs, with pharmacological and rapid chemical-genetic perturbation to interrogate primary transcriptional targets of BRD4 and MYC and define the response to BET bromodomain inhibitors (BETi). While BRD4 acts as a global co-activator of Pol2-dependent transcription in a BET bromodomain-dependent manner, therapeutic BETi doses deregulate a small set of hypersensitive target genes. In contrast to BRD4, MYC primarily acts as a selective transcriptional activator that controls basic metabolic processes such as ribosome biogenesis and de-novo purine synthesis across diverse cancer contexts. Beyond defining primary regulatory functions of BRD4 and MYC in cancer, our study establishes a simple, robust and scalable approach to dissect direct transcriptional targets of any gene or pathway.
2018-04-05 | GSE111457 | GEO
Project description:SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis [Quant-Seq]
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Project description:SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis [ChIP-Seq]
| PRJNA437112 | ENA
Project description:Defining direct targets of transcription factors and regulatory pathways is key to understanding their roles in physiology and disease. We combined SLAM-seq [thiol(SH)-linked alkylation for the metabolic sequencing of RNA], a method for direct quantification of newly synthesized messenger RNAs (mRNAs), with pharmacological and chemical-genetic perturbation in order to define regulatory functions of two transcriptional hubs in cancer, BRD4 and MYC, and to interrogate direct responses to BET bromodomain inhibitors (BETis). We found that BRD4 acts as general coactivator of RNA polymerase II-dependent transcription, which is broadly repressed upon high-dose BETi treatment. At doses triggering selective effects in leukemia, BETis deregulate a small set of hypersensitive targets including MYC. In contrast to BRD4, MYC primarily acts as a selective transcriptional activator controlling metabolic processes such as ribosome biogenesis and de novo purine synthesis. Our study establishes a simple and scalable strategy to identify direct transcriptional targets of any gene or pathway.
| S-EPMC6409205 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-04-05 | GSE111463 | GEO
Project description:SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis [SLAM-seq]
| PRJNA393189 | ENA
Project description:BRD4 is a key regulatory factor in multiple cancers and cellular stress responses with pleotropic functions. BRD4 regulates chromatin remodeling and transcription through its histone acetyltransferase (HAT) and kinase activities, respectively. The mechanism responsible for switching BRD4 from a chromatin to transcriptional regulator is currently unknown. Here, we report that in response to a broad range of stimuli, this switch is mediated by the JNK kinase which directly interacts with BRD4. JNK specifically phosphorylates human BRD4 at Ser1117, Thr1186 and Thr1212, triggering transient BRD4 release from chromatin. JNK phosphorylation of BRD4 halts its HAT-mediated chromatin regulation and activates its transcription-enhancing kinase function. BRD4 release from chromatin is necessary to toggle between its enzymatic activities: chromatin-bound BRD4 is kinase inactive and RNA Pol II-bound BRD4 does not acetylate chromatin. BRD4 release from chromatin augments its interaction with and phosphorylation of key transcriptional regulators RNA Pol II, PTEFb and c-MYC. The PP4 phosphatase dephosphorylates JNK phosphorylated BRD4 in the nucleoplasm, which promotes its interaction with RNA Pol II at transcriptionally active sites. Accordingly, JNK-mediated release of BRD4 from chromatin leads to significantly elevated transcription of BRD4-regulated immune and inflammatory response genes through enhanced BRD4-Pol II interaction at the promoters of these genes. JNK phosphorylation of BRD4 occurs during T-cell activation and is required for epithelial to mesenchymal transition (EMT) in prostate cancer cells. These findings thus characterize a novel mechanism that triggers the transition of BRD4 from a chromatin regulator to transcriptional activator during stress/immune/inflammatory responses and EMT.
2024-01-16 | MSV000093873 | MassIVE
Project description:The histone acetyl-reader BRD4 is an important regulator of chromatin structure and transcription, yet factors modulating its activity have remained elusive. Here we describe two complementary screens for genetic and physical interactors of BRD4, which converge on the folate pathway enzyme MTHFD1. We show that a fraction of MTHFD1 resides in the nucleus, where it is recruited to distinct genomic loci by direct interaction with BRD4. Inhibition of either BRD4 or MTHFD1 results in similar changes in nuclear metabolite composition and gene expression, and pharmacologic inhibitors of the two pathways synergize to impair cancer cell viability in vitro and in vivo. Our finding that MTHFD1 and other metabolic enzymes are chromatin-associated suggests a direct role for nuclear metabolism in the control of gene expression.
2019-04-04 | PXD012715 | Pride