Discovery and Characterization of Super-Enhancer-Associated Dependencies in Diffuse Large B Cell Lymphoma
Open accessAbstract
Diffuse large B cell lymphoma (DLBCL) is a biologically heterogeneous and clinically aggressive disease. Here, we explore the role of bromodomain and extra-terminal domain (BET) proteins in DLBCL, using integrative chemical genetics and functional epigenomics. We observe highly asymmetric loading of bromodomain 4 (BRD4) at enhancers, with approximately 33% of all BRD4 localizing to enhancers at 1.6% of occupied genes. These super-enhancers prove particularly sensitive to bromodomain inhibition, explaining the selective effect of BET inhibitors on oncogenic and lineage-specific transcriptional circuits. Functional study of genes marked by super-enhancers identifies DLBCLs dependent on OCA-B and suggests a strategy for discovering unrecognized cancer dependencies. Translational studies performed on a comprehensive panel of DLBCLs establish a therapeutic rationale for evaluating BET inhibitors in this disease.
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Mediator and BRD4 co-localise at very high levels at super-enhancers, long stretches of sequences with gene regulatory activity that generally drive greater levels of gene expression than regular enhancers.
“In particular, Mediator and BRD4 co-localise at very high levels at “super-enhancers” (SEs): long stretches of sequences with gene regulatory activity that generally drive greater levels of gene expression than regular enhancers [69–72].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [70]
The Results section (“Disproportionate binding of BRD4 to overloaded enhancers”; page unavailable) reports exceptionally high BRD4 loading at enhancers larger than typical enhancers. The Discussion (page unavailable) describes them as approximately 12-fold larger. Our copy does not establish co-localization with Mediator or show that these enhancers generally drive higher gene expression than regular enhancers; it reports greater sensitivity to BET inhibition instead. (LLM, conf=0.87)
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- Authors
- Chapuy, B., McKeown, M. R., Lin, C. Y., Monti, S., Roemer, M. G. M., Qi, J., Rahl, P. B., Sun, H. H., Yeda, K. T., Doench, J. G., Reichert, E., Kung, A. L., Rodig, S. J., Young, R. A., Shipp, M. A., & Bradner, J. E.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Boston University (US)
- Massachusetts Institute of Technology (US)
- Brigham and Women's Hospital (US)
- Broad Institute (US)
- Corresponding author
- Shipp, Margaret A.
- Bradner, James E.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2013-12
- Volume
- 24
- Issue
- 6
- Pages
- 777-790
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC4018722
- OpenAlex
- W2002395443
- Cited by
- 735
- References
- 2
- Citations by year
- 2026: 10 · 2025: 42 · 2024: 47 · 2023: 62 · 2022: 65 · 2021: 58 · 2020: 64 · 2019: 84 · 2018: 63 · 2017: 72 · 2016: 61 · 2015: 68 · 2014: 36 · 2013: 1
- FWCI
- 24.95
- Type
- journal article
- Language
- en
- Update notices
- erratum (2014-04-14)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- National Cancer Institute (R01CA176745, P50CA100707, R01CA152314, U54CA156732)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- diffuse large B-cell lymphoma, super-enhancers, BRD4, BET proteins, bromodomain inhibition, BET inhibitors, OCA-B, cancer dependency, transcriptional circuits, chemical genetics
- MeSH terms
- Bromodomain Containing Proteins, Azepines, DNA-Binding Proteins, Enhancer Elements, Genetic, Humans, Nuclear Proteins, Promoter Regions, Genetic, Transcription Factors, Transcription, Genetic, Triazoles, Trans-Activators, Genes, myc, Lymphoma, Large B-Cell, Diffuse, Cell Cycle Proteins, Proto-Oncogene Proteins c-bcl-6
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