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SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis [Quant-Seq]

ABSTRACT: SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis [Quant-Seq]

PROVIDER: PRJNA437106 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6809380.fastq.gz	Fastqsanger.gz
	SRR6809390.fastq.gz	Fastqsanger.gz
	SRR6809381.fastq.gz	Fastqsanger.gz
	SRR6809391.fastq.gz	Fastqsanger.gz
	SRR6809382.fastq.gz	Fastqsanger.gz

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SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis [Quant-Seq]

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.

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SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis [SLAM-seq]

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SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis

Project description:SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis

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SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis [ChIP-Seq]

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SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis [ChIP-Seq]

Project description:SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis [ChIP-Seq]

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SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis.

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.

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