ArticleEpigenetics & chromatin2019
BRD4 bimodal binding at promoters and drug-induced displacement at Pol II pause sites associates with I-BET sensitivity.
Article in Epigenetics & chromatin, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 46 citations in OpenAlex.
- Synergistic enhancement of PARP inhibition via small molecule UNI66-mediated suppression of BRD4-dependent transcription ofNAR cancer · 2025Article
- Differential responses of pulmonary vascular cells from PAH patients and controls to TNFα and the effect of the BET inhibitor JQ1.Respiratory research · 2023Article
- Modulation of cellular processes by histone and non-histone protein acetylation.Nature reviews. Molecular cell biology · 2022Review
- Article
- Genome-wide CRISPR-Cas9 screens identify mechanisms of BET bromodomain inhibitor sensitivity.iScience · 2021Article
- Article
- Anticancer Effects of I-BET151, an Inhibitor of Bromodomain and Extra-Terminal Domain Proteins.Frontiers in oncology · 2021Review
- Cis-acting lnc-eRNA SEELA directly binds histone H4 to promote histone recognition and leukemia progression.Genome biology · 2020Article
- Article
- Synthetic lethal combination targeting BET uncovered intrinsic susceptibility of TNBC to ferroptosis.Science advances · 2020Article
- Comparative structure-function analysis of bromodomain and extraterminal motif (BET) proteins in a gene-complementation system.The Journal of biological chemistry · 2020Article
- Small Molecules Targeting HATs, HDACs, and BRDs in Cancer Therapy.Frontiers in oncology · 2020Review
- DUB3 Facilitates Growth and Inhibits Apoptosis Through Enhancing Expression of EZH2 in Oral Squamous Cell Carcinoma.OncoTargets and therapy · 2020Article
- Review
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Authors and funding
12 authors at 6 institutions in 5 countries.
Funding
Abstract
backgroundDeregulated transcription is a major driver of diseases such as cancer. Bromodomain and extra-terminal (BET) proteins (BRD2, BRD3, BRD4 and BRDT) are chromatin readers essential for maintaining proper gene transcription by specifically binding acetylated lysine residues. Targeted displacement of BET proteins from chromatin, using BET inhibitors (I-BETs), is a promising therapy, especially for acute myeloid leukemia (AML), and evaluation of resistance mechanisms is necessary to optimize the clinical efficacy of these drugs.
resultsTo uncover mechanisms of intrinsic I-BET resistance, we quantified chromatin binding and displacement for BRD2, BRD3 and BRD4 after dose response treatment with I-BET151, in sensitive and resistant in vitro models of leukemia, and mapped BET proteins/I-BET interactions genome wide using antibody- and compound-affinity capture methods followed by deep sequencing. The genome-wide map of BET proteins sensitivity to I-BET revealed a bimodal pattern of binding flanking transcription start sites (TSSs), in which drug-mediated displacement from chromatin primarily affects BRD4 downstream of the TSS and prolongs the pausing of RNA Pol II. Correlation of BRD4 binding and drug-mediated displacement at RNA Pol II pause sites with gene expression revealed a differential behavior of sensitive and resistant tumor cells to I-BET and identified a BRD4 signature at promoters of sensitive coding and non-coding genes.
conclusionsWe provide evidence that I-BET-induced shift of Pol II pausing at promoters via displacement of BRD4 is a determinant of intrinsic I-BET sensitivity. This finding may guide pharmacological treatment to enhance the clinical utility of such targeted therapies in AML and potentially other BET proteins-driven diseases.
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