SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis
- PMID: 29622725
- PMCID: PMC6409205
- DOI: 10.1126/science.aao2793
SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis
Abstract
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.
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Conflict of interest statement
Figures
Comment in
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Taking aim at transcriptional regulator targets.Nat Rev Genet. 2018 Jun;19(6):328. doi: 10.1038/s41576-018-0010-5. Nat Rev Genet. 2018. PMID: 29686398 No abstract available.
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SLAMing transcription.Nat Chem Biol. 2018 Jun;14(6):525. doi: 10.1038/s41589-018-0074-8. Nat Chem Biol. 2018. PMID: 29769731 No abstract available.
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BRD4 and MYC-clarifying regulatory specificity.Science. 2018 May 18;360(6390):713-714. doi: 10.1126/science.aat6664. Science. 2018. PMID: 29773735 No abstract available.
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