期刊
SCIENCE
卷 360, 期 6390, 页码 800-805出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aao2793
关键词
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资金
- European Research Council [ERC-StG-336860, ERC-StG-338252]
- Austrian Science Fund [F4710, F4322, Y-733-B22 START, W127-B09]
- DOC fellowship of the Austrian Academy of Sciences
- Boehringer Ingelheim
- City of Vienna through the Vienna Business Agency
- Austrian Science Fund (FWF) [Y733, W1207] Funding Source: Austrian Science Fund (FWF)
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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