Affinage

BRD4

Bromodomain-containing protein 4 · UniProt O60885

Length
1362 aa
Mass
152.2 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BRD4 is a BET-family transcriptional regulator that couples acetylated chromatin recognition to RNA polymerase II elongation, integrating epigenetic readout with signal-dependent gene control across development, stress, and disease. Its tandem bromodomains bind acetylated histones and non-histone proteins (e.g., acetylated FOXO3a, ERG) to direct chromatin occupancy, while a C-terminal P-TEFb-interacting motif (CTM) is both necessary and sufficient for Pol II pause release independent of bromodomain function (PMID:37442129, PMID:24860166). BRD4 additionally possesses intrinsic kinase activity that phosphorylates MYC at Thr58 to promote its degradation and histone acetyltransferase activity inhibited by MYC, establishing a reciprocal feedback loop; its own activity is tuned by CK2/PP2A-mediated phosphorylation and PRMT1/2/4-mediated arginine methylation that enhances chromatin binding and DNA repair (PMID:32482868, PMID:36475791, PMID:27769352). Functionally, BRD4 associates with mitotic chromosomes to enable G2/M progression, recruits condensin II to insulate chromatin from DNA-damage signaling, represses autophagy genes via cooperation with G9a until displaced by AMPK/SIRT1 signaling, and forms isoform-specific phase-separated condensates at super-enhancers—with the short isoform being oncogenic and the long isoform tumor-suppressive in breast cancer (PMID:10938129, PMID:23728299, PMID:28525743, PMID:32203489, PMID:32446320).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2000 High

    Establishing that BRD4 remains chromatin-associated during mitosis and is required for G2/M progression answered the question of whether BET proteins have cell-cycle functions beyond transcriptional coactivation.

    Evidence Immunofluorescence and antibody microinjection in HeLa cells showing mitotic chromosome association and mitotic block

    PMID:10938129

    Open questions at the time
    • Mechanism by which BRD4 promotes G2/M entry not defined
    • Whether mitotic chromosome binding reflects bookmarking versus a direct cell-cycle signaling role was unresolved
  2. 2007 High

    Demonstrating that BRD4 resides in Mediator and P-TEFb complexes and stimulates Tat-independent transcription established it as a bona fide transcriptional coactivator linking acetylated chromatin to elongation.

    Evidence Biochemical fractionation and co-immunoprecipitation from nuclear extracts with HIV-1 transcription assays

    PMID:17329240

    Open questions at the time
    • Which domain of BRD4 contacts P-TEFb was unknown
    • Whether bromodomains are required for elongation function was untested
  3. 2009 High

    Identifying Aurora B as a direct transcriptional target of BRD4 connected BRD4's transcriptional activity to chromosome segregation fidelity and cytokinesis.

    Evidence RNAi knockdown and exogenous expression with promoter reporter assays in cancer cells and primary keratinocytes

    PMID:19596781

    Open questions at the time
    • Whether BRD4 directly occupies the Aurora B promoter was not shown by ChIP in this study
    • Generality to other mitotic kinase genes unclear
  4. 2013 High

    Discovering that a BRD4 isoform recruits condensin II to compact chromatin and attenuate DNA damage signaling revealed a non-transcriptional, chromatin-architectural function for BRD4.

    Evidence Genome-wide RNAi screen with gain/loss-of-function validation and cell-cycle checkpoint assays after irradiation

    PMID:23728299

    Open questions at the time
    • Which BRD4 isoform mediates condensin II recruitment was not fully defined structurally
    • Whether this function is separable from transcriptional roles at the same loci was unclear
  5. 2014 High

    Mapping the P-TEFb interaction domain (PID) of BRD4 and showing it shares Tat-like motifs that relieve Hexim1 inhibition defined the molecular basis of BRD4-mediated Pol II elongation stimulation.

    Evidence In vitro kinase assays, ITC binding measurements (Kd ~0.5 µM for CDK9), and systematic mutagenesis

    PMID:24860166

    Open questions at the time
    • Whether PID is sufficient for elongation in cells without bromodomains was untested
    • Structural basis of Hexim1 displacement not resolved
  6. 2016 High

    Multiple studies in 2016 revealed that BRD4 chromatin function is modulated by CK2/PP2A phosphorylation, operates in functional epistasis with DOT1L-mediated H3K79me2→H4ac at super-enhancers, and intersects with splicing and heat-stress pathways, broadening BRD4's role beyond simple acetyl-lysine reading.

    Evidence Kinase/phosphatase assays (CK2/PP2A), quantitative proteomics and ChIP-seq (DOT1L epistasis), RNA-seq after BRD4 depletion (splicing/stress)

    PMID:27294782 PMID:27536004 PMID:27769352

    Open questions at the time
    • Phosphorylation sites governing specific functions not comprehensively mapped
    • Whether splicing regulation is direct or secondary to transcriptional changes was unresolved
  7. 2017 High

    Showing that BRD4 cooperates with G9a to repress autophagy genes and is displaced by AMPK/SIRT1 during starvation established BRD4 as an active transcriptional repressor in nutrient sensing, not only an activator.

    Evidence BRD4 knockdown in vitro and in vivo with RNA-seq, ChIP, and signaling pathway dissection

    PMID:28525743

    Open questions at the time
    • Mechanism by which SIRT1 deacetylation leads to BRD4 eviction not fully defined
    • Whether G9a-BRD4 repressive complex operates beyond autophagy genes unknown
  8. 2019 High

    Multiple 2019 studies demonstrated that BRD4 serves as a signal-responsive chromatin effector: it undergoes TGF-β/p38 MAPK-dependent genome-wide redistribution at enhancers in fibrosis, physically interacts with nuclear MTHFD1 to couple folate metabolism to transcription, and forms transcription complexes with IRF1/P-TEFb to regulate necroptosis effector MLKL.

    Evidence ChIP-seq with TGF-β stimulation in cardiac fibroblasts; co-IP and metabolomics for MTHFD1 interaction; co-IP and cell death assays for IRF1/MLKL axis

    PMID:30644439 PMID:31133746 PMID:31409188

    Open questions at the time
    • How p38 MAPK modifies BRD4 or its partners to cause redistribution is unknown
    • MTHFD1-BRD4 interaction interface not structurally defined
    • Whether MLKL regulation is cell-type specific was not established
  9. 2020 High

    Three major mechanistic advances in 2020 established: (i) BRD4 possesses intrinsic kinase activity phosphorylating MYC-Thr58 to trigger MYC degradation while MYC reciprocally inhibits BRD4's HAT activity; (ii) the short isoform (BRD4-S) forms oncogenic phase-separated condensates at super-enhancers opposing the tumor-suppressive long isoform (BRD4-L); and (iii) ASXL3 bridges the BAP1 deubiquitinase complex to BRD4's ET domain at enhancers.

    Evidence In vitro kinase assays with phospho-specific antibodies and PROTAC degradation (kinase/HAT); isoform-specific manipulation with live imaging and phase separation assays (condensates); size exclusion chromatography, mass spectrometry, and ChIP-seq (ASXL3-ET domain)

    PMID:32203489 PMID:32446320 PMID:32482868 PMID:32669118

    Open questions at the time
    • BRD4 kinase domain identity/fold is undefined—no structural data
    • Whether BRD4-S condensates are functionally distinct from BRD4-L condensates at the same loci is unresolved
    • BAP1-ASXL3-BRD4 complex stoichiometry unknown
  10. 2021 High

    Studies in 2021 showed BRD4 cooperates with MED12 at enhancers upon Mediator kinase loss (creating a synthetic lethality with BET inhibition) and drives inflammatory super-enhancer formation via P300-dependent phase separation in macrophage foam cells, extending BRD4's enhancer-organizing role to immune and metabolic disease contexts.

    Evidence Functional genomic screens with ChIP-seq (CDK8/19-BET synthetic lethality); ChIP-seq with macrophage-specific Brd4 overexpression in vivo (atherosclerosis)

    PMID:34910943 PMID:35646539

    Open questions at the time
    • Whether MED12-BRD4 cooperation requires direct physical contact or is indirect via enhancer chromatin state is unclear
    • Contribution of phase separation versus linear chromatin binding in inflammatory gene activation not deconvolved
  11. 2022 High

    Discovery that PRMT2/4 methylate BRD4 at R179/181/183 to enhance chromatin binding and DNA repair gene regulation added a new layer of post-translational control to BRD4 function.

    Evidence In vitro methylation assays, mass spectrometry, ChIP-seq, R-to-K mutagenesis, and in vivo tumor models

    PMID:36475791

    Open questions at the time
    • How arginine methylation and CK2 phosphorylation integrate on BRD4 is unexplored
    • Whether arginine methylation affects BRD4 phase separation properties is unknown
  12. 2023 High

    Acute degron-mediated depletion and domain complementation definitively established that BRD4's bromodomains are dispensable for Pol II pause release, with the minimal C-terminal CTM being necessary and sufficient, resolving a long-standing question about the relationship between chromatin binding and elongation control.

    Evidence Rapid auxin-inducible degron depletion with genetic complementation by domain-deletion mutants, genome-wide ChIP-seq and RNA-seq

    PMID:37442129

    Open questions at the time
    • How CTM is recruited to specific promoters in the absence of bromodomains is unresolved
    • Whether bromodomain-independent pause release occurs in all cell types or is context-dependent

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include: the structural basis of BRD4's atypical kinase activity, how its multiple post-translational modifications (phosphorylation, arginine methylation, possibly lactylation) are coordinately regulated, and the in vivo functional distinction between BRD4 isoform-specific condensates versus linear chromatin binding at enhancers.
  • No crystal/cryo-EM structure of BRD4 kinase domain exists
  • Integrated PTM code for BRD4 regulation not systematically mapped
  • Causal contribution of phase separation versus conventional chromatin binding to target gene activation not resolved in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0042393 histone binding 5 GO:0098772 molecular function regulator activity 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0016740 transferase activity 1
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 2 GO:0005694 chromosome 2
Pathway
R-HSA-74160 Gene expression (Transcription) 8 R-HSA-162582 Signal Transduction 3 R-HSA-4839726 Chromatin organization 3 R-HSA-1640170 Cell Cycle 2 R-HSA-73894 DNA Repair 2 R-HSA-5357801 Programmed Cell Death 1 R-HSA-9612973 Autophagy 1
Partners
ASXL3CCNT1CDK9G9AMED12MTHFD1PRMT2PRMT4
Complex memberships
BAP1-ASXL3MediatorP-TEFb (CDK9/CyclinT1)

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 BRD4 binds preferentially to acetylated chromatin via its double bromodomains and is found in transcription complexes including the general cofactor Mediator and the P-TEFb elongation factor, stimulating HIV-1 transcription in a Tat-independent manner. BRD4 also serves as a cellular adaptor for papillomaviruses, anchoring viral genomes to mitotic chromosomes through interaction with virus-encoded E2 protein, facilitating viral genome segregation during mitosis. Biochemical fractionation, co-immunoprecipitation, transcription assays The Journal of biological chemistry High 17329240
2000 BRD4 (MCAP) associates with mitotic chromosomes during cell division at a time when most nuclear factors are released into the cytoplasm; it localizes preferentially to euchromatin and is absent from centromeres. Microinjection of anti-MCAP antibody into HeLa cell nuclei completely inhibited entry into mitosis without abrogating ongoing DNA replication, establishing BRD4's role in G2/M transition. Live cell imaging, immunofluorescence, microinjection of blocking antibody Molecular and cellular biology High 10938129
2013 A specific isoform of BRD4 functions as an endogenous inhibitor of DNA damage response signalling by recruiting the condensin II chromatin remodelling complex to acetylated histones through bromodomain interactions. Loss of this isoform results in relaxed chromatin, rapid cell-cycle checkpoint recovery, and enhanced survival after irradiation; gain of function compacts chromatin and attenuates DNA damage response signalling. High-content multiplex RNAi screen, gain-of-function/loss-of-function, chromatin fractionation, cell-cycle checkpoint assays Nature High 23728299
2014 BRD4 stimulates the kinase activity of P-TEFb for phosphorylation of the RNA polymerase II CTD. A P-TEFb interaction domain (PID) in BRD4 shares sequence motifs with HIV-1 Tat (RxL motif, polybasic cluster, C-terminal leucine motif). Mutation of these motifs diminished BRD4's stimulatory effect and abrogated its activation in the presence of Hexim1. BRD4 relieves P-TEFb inhibition by Hexim1 without mutual displacement of Cyclin T-binding domain; it binds directly to the kinase subunit CDK9 with Kd ~0.5 μM. In vitro kinase assay, mutagenesis, isothermal titration calorimetry, P-TEFb activity assays Nucleic acids research High 24860166
2009 BRD4 regulates Aurora B kinase expression at the transcriptional level. BRD4 knockdown in cancer cells and primary keratinocytes decreased Aurora B protein and mRNA levels, abolished its chromosomal distribution, and caused aberrant chromosome segregation and cytokinesis failures. Exogenous BRD4 expression stimulated Aurora B promoter reporter activity and upregulated endogenous Aurora B expression. RNAi knockdown, luciferase reporter assay, immunofluorescence, Western blot Molecular and cellular biology High 19596781
2015 ARV-825, a PROTAC that recruits BRD4 to the E3 ubiquitin ligase cereblon, induces fast, efficient, and prolonged proteasome-mediated degradation of BRD4, more effectively suppressing c-MYC levels and downstream signaling compared to BRD4 inhibitors alone. BRD4 inhibitors (without degradation) lead to robust BRD4 protein accumulation. PROTAC degrader design, Western blot, cell viability assay, flow cytometry apoptosis assay Chemistry & biology High 26051217
2016 BRD4 and DOT1L exist in separate protein complexes in native cells. DOT1L, via dimethylated histone H3K79, facilitates histone H4 acetylation, which in turn regulates BRD4 binding to chromatin. Genetic or pharmacological disruption of either protein shows marked synergistic activity against MLL leukemia, indicating functional interdependence at highly transcribed genes near super-enhancers. Quantitative proteomics, chemoproteomics, biochemical fractionation, ChIP-seq, genetic epistasis Nature structural & molecular biology High 27294782
2017 BRD4 and the methyltransferase G9a repress a transcriptional program promoting autophagy and lysosome biogenesis independently of TFEB/TFE3/MITF. During starvation, a signaling cascade involving AMPK and histone deacetylase SIRT1 displaces chromatin-bound BRD4, instigating autophagy gene activation and cell survival. BRD4 knockdown in vitro and in vivo, RNA-seq, ChIP, signaling pathway analysis Molecular cell High 28525743
2020 BRD4 phosphorylates MYC at Thr58, leading to MYC ubiquitination and degradation, thereby regulating MYC target genes. BRD4 degradation (not merely inhibition) results in increased MYC protein levels. MYC in turn inhibits BRD4's histone acetyltransferase (HAT) activity, creating a feedback loop. ERK1 inhibits BRD4 kinase activity, counteracting MYC destabilization. In vitro kinase assay, phospho-specific antibodies, mutagenesis, Western blot, BRD4 PROTAC degradation Proceedings of the National Academy of Sciences of the United States of America High 32482868
2020 The BRD4 short isoform (BRD4-S) is oncogenic while the long isoform (BRD4-L) is tumor-suppressive in breast cancer. BRD4-S forms nuclear condensates with liquid-like properties that colocalize with BRD4-L, MED1, and H3K27ac sites. BRD4-S condensation is mediated by intrinsically disordered regions and bromodomain binding to DNA and acetylated chromatin; BRD4-S phosphorylation diminishes condensation. Isoform-specific knockdown, transgene expression, RNA-seq, ChIP-seq, CUT&RUN, live cell imaging, phase separation assays Nature structural & molecular biology High 32203489
2020 BRD4 short and long isoforms have opposing functions in breast cancer: BRD4-S is oncogenic and BRD4-L is tumor-suppressive. BRD4-S co-regulates the Engrailed-1 (EN1) homeobox transcription factor and together modulates extracellular matrix/matrisome gene networks via enhancer regulation, particularly in triple-negative breast cancer. Isoform-specific knockdown, transgene expression, RNA-seq, ChIP-seq, CUT&RUN, in vivo tumor formation assays Molecular cell High 32446320
2023 BRD4 bromodomains are dispensable for RNA polymerase II pause release. A minimal C-terminal BRD4 fragment containing the P-TEFb-interacting C-terminal motif (CTM) is both necessary and sufficient to mediate Pol II pause release in the absence of full-length BRD4, demonstrating that BRD4-PTEFb regulates transcription independently of bromodomain-mediated chromatin association. Rapid depletion (degron), genetic complementation with domain deletion mutants, ChIP-seq, RNA-seq Molecular cell High 37442129
2016 BRD4 phosphorylation by CK2 and dephosphorylation by PP2A modulates its function in chromatin targeting, factor recruitment, and cancer progression. Phospho-BRD4 also regulates papillomavirus E1- and E2-dependent origin replication and viral gene transcription. Kinase/phosphatase assays, viral replication assays, transcription assays Drug discovery today. Technologies Medium 27769352
2019 MTHFD1 (a folate pathway enzyme) physically interacts with BRD4, with a fraction of MTHFD1 residing in the nucleus where it is recruited to distinct genomic loci. Inhibition of either BRD4 or MTHFD1 results in similar changes in nuclear metabolite composition and gene expression, and pharmacological inhibitors of the two pathways synergize to impair cancer cell viability. Genetic and physical interaction screens, co-IP, ChIP-seq, metabolomics, in vitro and in vivo drug synergy Nature genetics High 31133746
2016 BRD4 interacts with the splicing machinery and heat shock factor 1 (HSF1); under heat stress BRD4 is recruited to nuclear stress bodies and non-coding SatIII RNA transcripts are upregulated. BRD4 depletion increases intron retention and splicing inhibition, leading to decreased mRNA abundance of affected transcripts, establishing a role for BRD4 in regulating splicing during heat stress. RNA-seq, Co-IP (BRD4–HSF1 interaction), BRD4 knockdown, immunofluorescence Nucleic acids research Medium 27536004
2019 BRD4 functions as an effector of TGF-β signaling in cardiac fibroblasts. ChIP-seq shows BRD4 undergoes stimulus-dependent genome-wide redistribution, becoming enriched on a subset of enhancers and super-enhancers upon TGF-β stimulation, leading to RNA Pol II activation and fibrosis gene expression. Dynamic chromatin targeting of BRD4 is controlled in part by p38 MAPK. ChIP-seq, RNA-seq, mass spectrometry, primary fibroblast assays, in vivo mouse model with JQ1 Circulation research High 31409188
2022 PRMT2 and PRMT4 methylate BRD4 at R179, R181, and R183. This arginine methylation promotes BRD4 recruitment to acetylated histones/chromatin to control a transcriptional program, and is induced by DNA damage to promote BRD4 chromatin binding for DNA repair. Deficiency in BRD4 arginine methylation suppresses tumor growth and sensitizes cells to BET inhibitors. Co-IP, in vitro methylation assay, ChIP-seq, mutagenesis, mass spectrometry Science advances High 36475791
2023 PRMT1 asymmetrically methylates BRD4 at R179/181/183, which is antagonized by the demethylase JMJD6. PRMT1-mediated BRD4 methylation promotes BRD4 phosphorylation; cells expressing BRD4 R179/181/183K mutant show reduced ovarian cancer metastasis. BRD4 arginine methylation is associated with TGF-β signaling. Co-IP, in vitro methylation assay, mutagenesis, mass spectrometry, in vivo xenograft Cell death & disease High 37737256
2020 ASXL3 directly interacts with BRD4's extra-terminal (ET) domain via a novel BRD4 binding motif (BBM), functioning as an adaptor protein that bridges the BAP1 complex to BRD4 and maintains BRD4 chromatin occupancy at active enhancers in SCLC. Genetic depletion of ASXL3 causes genome-wide reduction of H3K27Ac and BRD4-dependent gene expression. Size exclusion chromatography, mass spectrometry, Western blot, ChIP-seq, RNA-seq Genome medicine High 32669118
2016 Truncated ERG (ERGΔ39), encoded by the TMPRSS2-ERG prostate cancer fusion, binds to bromodomain-1 (BD1) of BRD4. An acetylation-mimicking mutation in ERG augments the ERG-BRD4 interaction and enhances ERG-mediated invasion of prostate cancer cells. ERG and BRD4 co-occupy substantial genomic binding sites. Co-IP, ChIP-seq meta-analysis, mutagenesis, invasion assay, BET inhibitor competition Oncotarget Medium 27223260
2014 BRD4 associates with BRG1 (SMARCA4/SWI-SNF) at Nanog regulatory regions to regulate Nanog expression in mouse embryonic stem cells. Inhibition of BRD4 by chemical inhibitor, siRNA, or dominant-negative approach suppresses Nanog expression and abolishes ESC self-renewal ability. ChIP, Co-IP, RNAi knockdown, dominant-negative expression, reporter assay Cell death and differentiation Medium 25146928
2019 BRD4 inhibition reduces Snail protein stability and transcription in breast cancer cells. Protein kinase D1 (PRKD1) is responsible for BRD4-regulated Snail protein stability by triggering phosphorylation at Ser11 of Snail and inducing proteasome-mediated degradation. BRD4 also suppresses Gli1 expression, a transductor of Hedgehog required for SNAI1 transcription. Western blot, phospho-specific antibodies, ChIP, luciferase reporter, RNAi knockdown, in vivo xenograft Cell death and differentiation Medium 31114028
2019 BRD4 binds to the HOTAIR promoter (as shown by ChIP) and directly regulates lncRNA expression in glioblastoma. BET inhibitor I-BET151 reduces HOTAIR levels, and HOTAIR overexpression abrogates the antiproliferative activity of BET inhibition. ChIP-qPCR, single-molecule sequencing, BET inhibitor treatment, HOTAIR overexpression rescue Proceedings of the National Academy of Sciences of the United States of America Medium 26111795
2018 Acetylated FOXO3a (following AKT inhibitor treatment) recognizes the BD2 domain of BRD4, recruits the BRD4/RNAPII complex to the CDK6 gene promoter, and induces CDK6 transcription leading to AKT inhibitor resistance. Pharmacological inhibition of either BRD4/FOXO3a association or CDK6 overcomes resistance. Co-IP, ChIP, luciferase reporter, RNAi, in vitro and in vivo drug combination studies Nature communications Medium 30518851
2019 BRD4 forms a transcription complex with IRF1, P-TEFb, and RNA polymerase II to regulate expression of MLKL, and BET inhibitors interfere with this complex formation to protect cells from necroptosis in the TNFα/Smac-mimetic/Z-VAD-FMK model. Co-IP, small molecule screen, Western blot, necroptosis cell death assays Cell death and differentiation Medium 30644439
2021 BRD4 cooperates with MED12 at enhancer elements upon CDK8/19 loss. Loss of Mediator kinase leads to increased MED12 and BRD4 co-occupancy at enhancers and increased dependence on BET proteins for transcription of cell-essential genes, demonstrating a synthetic lethal interaction between Mediator kinase and BET proteins. Functional genomic screen, pharmacological inhibition, ChIP-seq, RNA-seq, genetic depletion Molecular cell High 34910943
2020 BRD4 inhibition suppresses HIF1α expression, which in turn reduces CSF1 secretion by tumor cells and blocks proliferation of tumor-associated macrophages, revealing a BRD4→HIF1α→CSF1 axis by which BRD4 inhibition affects the tumor microenvironment. Western blot, ChIP, cytokine ELISA, in vivo syngeneic/xenograft models Nature communications Medium 32286255
2021 BRD4 associates with the Nox4 promoter together with p300 acetyltransferase and acetylated H4K16 in lung fibroblasts stimulated with TGF-β1. BET inhibition interferes with this Brd4/p300/H4K16ac complex at the Nox4 promoter to downregulate Nox4 gene expression. ChIP, Co-IP, gene expression analysis, BET inhibitor treatment JCI insight Medium 32544088
2021 A natural product PCG directly binds to BRD4, inhibits BRD4 phase separation, converts dynamic BRD4 nuclear condensates into static aggregates, and effectively shuts down transcription of BRD4-dependent genes. BRD4 phase separation at super-enhancers is thus identified as a functional mechanism. Direct binding assay, live cell imaging, phase separation in vitro assay, transcription assays iScience Medium 35072011
2024 BRD4 plays a pivotal role in histone lactylation in astrocytes after subarachnoid hemorrhage. BRD4 silencing in astrocytes significantly reduces H4K8la lactylation, thereby aggravating A1 polarization of astrocytes and affecting neural function recovery in mice after SAH. BRD4 siRNA knockdown in vitro and in vivo, histone lactylation assay, astrocyte polarization assays, mouse SAH model Journal of neuroinflammation Medium 39080649
2017 BRD4 is required for myogenic differentiation, binding to the Myog promoter coincident with increased H3K27 acetylation during C2C12 myoblast differentiation. BRD3 knockdown conversely enhances myogenic differentiation, establishing distinct opposing functions of BRD3 and BRD4 in skeletal myogenesis. RNAi knockdown, ChIP, small molecule inhibitor screen, primary myoblast differentiation assays Scientific reports Medium 28733670
2021 BRD4 functions as a transcriptional activator downstream of ox-LDL-mediated P300 activation; P300 promotes BRD4 binding to promoter regions of inflammatory genes, and BRD4-dependent super-enhancer formation (involving liquid-liquid phase separation) drives inflammatory gene expression in macrophage foam cells in atherosclerosis. ChIP-seq, Co-IP, siRNA knockdown, in vivo mouse model with macrophage-specific Brd4 overexpression Acta pharmaceutica Sinica. B Medium 35646539

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4. Chemistry & biology 877 26051217
1999 Transcription activation by catabolite activator protein (CAP). Journal of molecular biology 654 10550204
2018 BRD4 and Cancer: going beyond transcriptional regulation. Molecular cancer 574 30466442
2007 The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation. The Journal of biological chemistry 554 17329240
2013 The bromodomain protein Brd4 insulates chromatin from DNA damage signalling. Nature 268 23728299
2000 A bromodomain protein, MCAP, associates with mitotic chromosomes and affects G(2)-to-M transition. Molecular and cellular biology 253 10938129
2020 Antibody-PROTAC Conjugates Enable HER2-Dependent Targeted Protein Degradation of BRD4. ACS chemical biology 249 32338867
2017 Bromodomain Protein BRD4 Is a Transcriptional Repressor of Autophagy and Lysosomal Function. Molecular cell 206 28525743
2004 Cap-dependent and cap-independent translation in eukaryotic systems. Gene 205 15145049
2014 Brd4 activates P-TEFb for RNA polymerase II CTD phosphorylation. Nucleic acids research 190 24860166
2001 Suppression of cap-dependent translation in mitosis. Genes & development 187 11511540
2015 The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation. Proceedings of the National Academy of Sciences of the United States of America 184 26111795
2009 Regulation of mRNA cap methylation. The Biochemical journal 168 20025612
2014 Cap-binding complex (CBC). The Biochemical journal 166 24354960
2019 Dynamic Chromatin Targeting of BRD4 Stimulates Cardiac Fibroblast Activation. Circulation research 152 31409188
2020 Opposing Functions of BRD4 Isoforms in Breast Cancer. Molecular cell 139 32446320
2020 Potent BRD4 inhibitor suppresses cancer cell-macrophage interaction. Nature communications 138 32286255
2020 Roles of the BRD4 short isoform in phase separation and active gene transcription. Nature structural & molecular biology 132 32203489
2010 Enzymology of RNA cap synthesis. Wiley interdisciplinary reviews. RNA 129 21956912
2020 MYC protein stability is negatively regulated by BRD4. Proceedings of the National Academy of Sciences of the United States of America 126 32482868
2018 Targeting Brd4 for cancer therapy: inhibitors and degraders. MedChemComm 124 30542529
2020 Bardoxolone conjugation enables targeted protein degradation of BRD4. Scientific reports 108 32968148
2021 Autophagy enhanced by curcumin ameliorates inflammation in atherogenesis via the TFEB-P300-BRD4 axis. Acta pharmaceutica Sinica. B 107 35646539
2019 Emerging roles of and therapeutic strategies targeting BRD4 in cancer. Cellular immunology 105 30832981
2008 Capturing protein tails by CAP-Gly domains. Trends in biochemical sciences 95 18835717
2019 Inhibition of BRD4 suppresses the malignancy of breast cancer cells via regulation of Snail. Cell death and differentiation 94 31114028
2016 Functional interdependence of BRD4 and DOT1L in MLL leukemia. Nature structural & molecular biology 92 27294782
2020 The Cap-Snatching Mechanism of Bunyaviruses. Trends in microbiology 89 31948728
2017 Epigenetic targeting of bromodomain protein BRD4 counteracts cancer cachexia and prolongs survival. Nature communications 88 29167426
2004 'Cap-tabolism'. Trends in biochemical sciences 87 15362228
2018 Targeting the BRD4/FOXO3a/CDK6 axis sensitizes AKT inhibition in luminal breast cancer. Nature communications 81 30518851
2012 Two faces of brd4: mitotic bookmark and transcriptional lynchpin. Transcription 77 23131666
2019 MTHFD1 interaction with BRD4 links folate metabolism to transcriptional regulation. Nature genetics 70 31133746
2022 Regulation of programmed cell death by Brd4. Cell death & disease 69 36539410
2015 BRD4 Structure-Activity Relationships of Dual PLK1 Kinase/BRD4 Bromodomain Inhibitor BI-2536. ACS medicinal chemistry letters 67 26191363
2014 Brd4 and HEXIM1: multiple roles in P-TEFb regulation and cancer. BioMed research international 65 24592384
2020 Targeting BRD4 prevents acute gouty arthritis by regulating pyroptosis. International journal of biological sciences 64 33162822
2014 BRD4 regulates Nanog expression in mouse embryonic stem cells and preimplantation embryos. Cell death and differentiation 61 25146928
2019 Interrogating Histone Acetylation and BRD4 as Mitotic Bookmarks of Transcription. Cell reports 60 30970245
2020 Novel strategies targeting bromodomain-containing protein 4 (BRD4) for cancer drug discovery. European journal of medicinal chemistry 58 32502863
2020 Brd4-p300 inhibition downregulates Nox4 and accelerates lung fibrosis resolution in aged mice. JCI insight 57 32544088
2009 Regulation of aurora B expression by the bromodomain protein Brd4. Molecular and cellular biology 57 19596781
2022 BRD4 and MYC: power couple in transcription and disease. The FEBS journal 56 35866356
2020 The multifaceted eukaryotic cap structure. Wiley interdisciplinary reviews. RNA 54 33300197
2021 BRD4 in physiology and pathology: ''BET'' on its partners. BioEssays : news and reviews in molecular, cellular and developmental biology 53 34697817
2019 Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cells. Neoplasia (New York, N.Y.) 52 31734632
2017 Synthesis and evaluation of novel dual BRD4/HDAC inhibitors. Bioorganic & medicinal chemistry 52 28549889
2020 ASXL3 bridges BRD4 to BAP1 complex and governs enhancer activity in small cell lung cancer. Genome medicine 51 32669118
2016 The bromodomain protein BRD4 regulates splicing during heat shock. Nucleic acids research 50 27536004
2006 The Moraxella catarrhalis autotransporter McaP is a conserved surface protein that mediates adherence to human epithelial cells through its N-terminal passenger domain. Infection and immunity 49 17088358
2021 BRD4 inhibition sensitizes cervical cancer to radiotherapy by attenuating DNA repair. Oncogene 47 33712705
2019 A patent review of BRD4 inhibitors (2013-2019). Expert opinion on therapeutic patents 47 31815566
2023 Distinct layers of BRD4-PTEFb reveal bromodomain-independent function in transcriptional regulation. Molecular cell 46 37442129
2016 Phospho-BRD4: transcription plasticity and drug targeting. Drug discovery today. Technologies 46 27769352
2016 Involvement of Brd4 in different steps of the papillomavirus life cycle. Virus research 46 27965149
1996 Mammalian CAP interacts with CAP, CAP2, and actin. Journal of cellular biochemistry 46 8761950
2004 Brd4: tethering, segregation and beyond. Trends in microbiology 45 15539109
2016 BET bromodomain-mediated interaction between ERG and BRD4 promotes prostate cancer cell invasion. Oncotarget 44 27223260
2015 Targeting bromodomain-containing protein 4 (BRD4) benefits rheumatoid arthritis. Immunology letters 44 26093279
2010 The root cap at the forefront. Comptes rendus biologies 43 20371108
2006 Adenosine kinase modulates root gravitropism and cap morphogenesis in Arabidopsis. Plant physiology 43 16891550
2022 Post-Translational Modifications of BRD4: Therapeutic Targets for Tumor. Frontiers in oncology 40 35402244
2022 Bromodomain-containing protein 4 (BRD4) as an epigenetic regulator of fatty acid metabolism genes and ferroptosis. Cell death & disease 40 36309482
2021 Brd4-bound enhancers drive cell-intrinsic sex differences in glioblastoma. Proceedings of the National Academy of Sciences of the United States of America 40 33850013
2020 Discovery of selective HDAC/BRD4 dual inhibitors as epigenetic probes. European journal of medicinal chemistry 40 33077265
2023 Cholesterol-Amino-Phosphate (CAP) Derived Lipid Nanoparticles for Delivery of Self-Amplifying RNA and Restoration of Spermatogenesis in Infertile Mice. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 39 36748274
2022 BRD9 regulates interferon-stimulated genes during macrophage activation via cooperation with BET protein BRD4. Proceedings of the National Academy of Sciences of the United States of America 39 34983841
2022 Arginine methylation of BRD4 by PRMT2/4 governs transcription and DNA repair. Science advances 39 36475791
2018 Dual BRD4 and AURKA Inhibition Is Synergistic against MYCN-Amplified and Nonamplified Neuroblastoma. Neoplasia (New York, N.Y.) 37 30153557
2017 BRD3 and BRD4 BET Bromodomain Proteins Differentially Regulate Skeletal Myogenesis. Scientific reports 37 28733670
2024 Lactylation of histone by BRD4 regulates astrocyte polarization after experimental subarachnoid hemorrhage. Journal of neuroinflammation 35 39080649
2024 Cotargeting CDK4/6 and BRD4 Promotes Senescence and Ferroptosis Sensitivity in Cancer. Cancer research 33 38277141
2020 The therapeutic potential of BRD4 in cardiovascular disease. Hypertension research : official journal of the Japanese Society of Hypertension 33 32409773
2018 BRD4 inhibitor JQ1 inhibits and reverses mechanical injury-induced corneal scarring. Cell death discovery 32 30062054
2023 The BRD4-NUT Fusion Alone Drives Malignant Transformation of NUT Carcinoma. Cancer research 31 37819236
2017 BRD4 is a newly characterized transcriptional regulator that represses autophagy and lysosomal function. Autophagy 31 28837371
2021 MED12 and BRD4 cooperate to sustain cancer growth upon loss of mediator kinase. Molecular cell 30 34910943
2019 The bromodomain protein BRD4 positively regulates necroptosis via modulating MLKL expression. Cell death and differentiation 30 30644439
2021 Dual-target inhibitors of bromodomain-containing protein 4 (BRD4) in cancer therapy: Current situation and future directions. Drug discovery today 29 34438075
2016 mRNA Cap Methylation in Pluripotency and Differentiation. Cell reports 28 27452456
2023 YAP/BRD4-controlled ROR1 promotes tumor-initiating cells and hyperproliferation in pancreatic cancer. The EMBO journal 27 37096681
2020 A Bromodomain-Containing Protein 4 (BRD4) Inhibitor Suppresses Angiogenesis by Regulating AP-1 Expression. Frontiers in pharmacology 27 32765266
2017 BRD4 promotes p63 and GRHL3 expression downstream of FOXO in mammary epithelial cells. Nucleic acids research 27 27980063
2022 Engineering CpG-ASO-Pt-Loaded Macrophages (CAP@M) for Synergistic Chemo-/Gene-/Immuno-Therapy. Advanced healthcare materials 26 35668035
2020 ARV-825-induced BRD4 protein degradation as a therapy for thyroid carcinoma. Aging 26 32163373
2019 B7-H3 is regulated by BRD4 and promotes TLR4 expression in pancreatic ductal adenocarcinoma. The international journal of biochemistry & cell biology 26 30664982
2021 Discovery of novel 4-phenylquinazoline-based BRD4 inhibitors for cardiac fibrosis. Acta pharmaceutica Sinica. B 25 35127386
2024 Cold atmospheric plasma (CAP): a revolutionary approach in dermatology and skincare. European journal of medical research 24 39367460
2023 Methylation of BRD4 by PRMT1 regulates BRD4 phosphorylation and promotes ovarian cancer invasion. Cell death & disease 24 37737256
2021 Modulation of BRD4 in HIV epigenetic regulation: implications for finding an HIV cure. Retrovirology 24 33413475
2017 The Essential Transcriptional Function of BRD4 in Acute Myeloid Leukemia. Cold Spring Harbor symposia on quantitative biology 24 28174254
2024 The mechanism of mRNA cap recognition. Nature 23 39663447
2023 Arabidopsis DXO1 activates RNMT1 to methylate the mRNA guanosine cap. Nature communications 22 36639378
2022 Therapeutic Targeting of EZH2 and BET BRD4 in Pediatric Rhabdoid Tumors. Molecular cancer therapeutics 22 35247919
2020 RSV Reprograms the CDK9•BRD4 Chromatin Remodeling Complex to Couple Innate Inflammation to Airway Remodeling. Viruses 22 32331282
2016 Chromatin Landscape of the IRF Genes and Role of the Epigenetic Reader BRD4. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 22 27379869
2023 Bromodomain-containing protein 4 (BRD4): a key player in inflammatory bowel disease and potential to inspire epigenetic therapeutics. Expert opinion on therapeutic targets 21 36710583
2021 miR-766-5p Targets Super-Enhancers by Downregulating CBP and BRD4. Cancer research 21 34353856
2019 CAPAM: The mRNA Cap Adenosine N6-Methyltransferase. Trends in biochemical sciences 21 30679132
2021 A natural product targets BRD4 to inhibit phase separation and gene transcription. iScience 20 35072011