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BRD4

Bromodomain-containing protein 4 · UniProt O60885

Length
1362 aa
Mass
152.2 kDa
Annotated
2026-06-09
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BRD4 is a chromatin-associated regulator of transcription that reads acetylated histones through its double bromodomains and couples enhancer/super-enhancer activity to RNA polymerase II elongation by recruiting the P-TEFb elongation factor (PMID:17329240, PMID:27294782). Its association with mitotic chromosomes—where it persists while most regulatory factors dissociate—underlies an essential role in the G2/M transition, and it serves as a cellular tether for viral genomes during mitosis (PMID:10938129, PMID:17329240). BRD4 drives transcriptional pause release through a C-terminal motif (CTM) that binds P-TEFb; this bromodomain-less CTM fragment is necessary and sufficient for Pol II pause release, defining a chromatin-reading-independent transcriptional function, and the CTM–P-TEFb axis prevents R-loop accumulation and transcription–replication conflicts (PMID:37442129, PMID:32966794). Beyond reading acetylation, BRD4 possesses intrinsic kinase activity that phosphorylates MYC at Thr58 to trigger its degradation and acts on RNA Pol II, as well as histone acetyltransferase activity; JNK-mediated phosphorylation at Thr1186/Thr1212 switches BRD4 between a chromatin-bound HAT-active state and a promoter-associated kinase-active state (PMID:32482868, PMID:39454579). BRD4 assembles liquid-like nuclear condensates at acetylated super-enhancers, nucleated by intrinsically disordered regions and bromodomain–chromatin contacts and tuned by phosphorylation, providing selective compartmentalization at multivalent acetylated chromatin (PMID:32203489, PMID:38656803). BRD4 is regulated post-translationally by CK2 phosphorylation, which promotes a phosphorylation-dependent dimerization, and by PRMT1/2/4 arginine methylation at R179/181/183, which enhances chromatin recruitment for transcription and DNA repair and is antagonized by JMJD6 (PMID:34754068, PMID:36475791, PMID:37737256). It supports genome integrity and architecture by recruiting condensin II to insulate chromatin from DNA damage signaling, promoting double-strand-break resection and homologous recombination via SWI/SNF, and stabilizing NIPBL/cohesin to enable loop extrusion and genome folding (PMID:23728299, PMID:35641523, PMID:34611363). Two isoforms have opposing roles in breast cancer, with BRD4-S oncogenic and BRD4-L tumor-suppressive, and BRD4 can be eliminated by cereblon-based PROTACs that more effectively suppress MYC than bromodomain inhibition alone (PMID:32446320, PMID:26051217).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2000 High

    Established that BRD4 is a chromatin-retained factor with a cell-cycle function, answering whether it acts during mitosis rather than only in interphase transcription.

    Evidence Immunofluorescence/live-cell imaging plus microinjection of neutralizing anti-BRD4 antibody and cell cycle analysis in HeLa cells

    PMID:10938129

    Open questions at the time
    • Molecular partners mediating mitotic chromosome retention not defined
    • Link to transcriptional function not yet established at this stage
  2. 2007 Medium

    Defined the core transcriptional mechanism—bromodomain reading of acetylated chromatin and recruitment of P-TEFb/Mediator—and a viral-tethering adaptor role, framing BRD4 as a transcription elongation factor.

    Evidence Co-immunoprecipitation, transcriptional reporter assays, and biochemical fractionation (review synthesizing prior experimental work)

    PMID:17329240

    Open questions at the time
    • Domain dependence of P-TEFb recruitment not dissected
    • Quantitative contribution to elongation versus initiation unresolved
  3. 2013 High

    Showed BRD4 actively restrains DNA damage signaling via condensin II recruitment, extending its role from transcription to chromatin compaction and the DDR.

    Evidence High-content RNAi screen with loss/gain-of-function, chromatin compaction and irradiation survival assays

    PMID:23728299

    Open questions at the time
    • Isoform specificity of the effect not fully resolved
    • Direct condensin II contact interface not mapped
  4. 2015 High

    Demonstrated that targeted degradation of BRD4 differs functionally from bromodomain inhibition, establishing a degrader strategy and revealing inhibitor-induced protein accumulation.

    Evidence PROTAC (ARV-825)-mediated cereblon recruitment, western blot, viability and apoptosis assays across cell lines

    PMID:26051217

    Open questions at the time
    • Degron site preferences on BRD4 not defined
    • In vivo durability of degradation not assessed here
  5. 2016 High

    Connected BRD4 chromatin binding to upstream histone modifications (DOT1L/H3K79me2-driven H4 acetylation) and to heat-stress splicing and CK2/PP2A regulation, broadening its regulatory inputs.

    Evidence Quantitative/chemoproteomics, fractionation, ChIP-seq, genetics (DOT1L); Co-IP and RNA-seq (HSF1/splicing); kinase/phosphatase assays (CK2/PP2A)

    PMID:27294782 PMID:27536004 PMID:27769352

    Open questions at the time
    • Whether CK2/PP2A regulation and splicing roles share a common mechanism unclear
    • Direct vs indirect effects of DOT1L on BRD4 occupancy not fully separated
  6. 2017 High

    Revealed context-specific and repressive transcriptional roles—silencing autophagy/lysosomal genes via G9a and driving myogenic gene programs—showing BRD4 is not uniformly an activator.

    Evidence Knockdown, ChIP, reciprocal Co-IP, AMPK/SIRT1 manipulation (autophagy); BET-protein-specific RNAi and ChIP at Myog (myogenesis)

    PMID:28525743 PMID:28733670

    Open questions at the time
    • Determinants selecting activation versus repression at a given locus unknown
    • BRD4 vs BRD3 functional divergence mechanism unresolved
  7. 2018 Medium

    Linked BRD4 to replication-checkpoint control through association with CDC6 and CHK1 signaling, adding a replication-stress arm to its genome-maintenance functions.

    Evidence Co-IP, JQ1/AZD5153 inhibition, CHK1 phosphorylation and replication assays, xenografts

    PMID:29636547

    Open questions at the time
    • Direct vs transcription-mediated effect on the checkpoint not separated
    • Reciprocal validation of BRD4-CDC6 interaction limited
  8. 2019 High

    Defined signal-responsive genome-wide redistribution and tissue-specific requirements of BRD4, plus a nuclear metabolic partnership with MTHFD1, establishing it as a context-dependent enhancer effector.

    Evidence ChIP-seq/RNA-seq/mass-spec in TGF-β-stimulated fibroblasts; conditional Brd4 KO mice (hematopoiesis/macrophages); interaction screens and metabolomics (MTHFD1); zebrafish ZGA gain/loss-of-function with P300; Co-IP of BRD4-IRF1-P-TEFb-RNAPII at MLKL

    PMID:30644439 PMID:30842097 PMID:31133746 PMID:31211993 PMID:31409188

    Open questions at the time
    • Why some super-enhancers are BRD4-independent (compensatory) is unexplained
    • Mechanism of MTHFD1 nuclear recruitment to specific loci not defined
  9. 2020 High

    Established BRD4 as a phase-separating, dual-isoform protein with intrinsic MYC-directed kinase activity and an R-loop-suppressing CTM–P-TEFb function, integrating biophysics, enzymology, and genome stability.

    Evidence FRAP/live imaging and isoform-specific KD (condensates, isoform functions); in vitro kinase/HAT and ubiquitination assays (MYC Thr58); DRIP-seq and domain mutants (R-loops); inhibitor/HIF1α/CSF1 tumor models

    PMID:32203489 PMID:32286255 PMID:32446320 PMID:32482868 PMID:32966794

    Open questions at the time
    • Catalytic identity/structure of the BRD4 kinase module not resolved
    • How condensate formation mechanistically couples to elongation unclear
  10. 2021 High

    Mapped post-translational and architectural control of BRD4—CK2-driven dimerization, arginine methylation–regulated recruitment, NIPBL/cohesin stabilization for genome folding, and adaptor-mediated chromatin retention—plus differentiation roles.

    Evidence Integrative structural biology and CK2 assays (dimerization); in vitro methylation/Co-IP/ChIP-seq with R-to-K mutants (PRMT1/2/4, JMJD6); Co-IP, Hi-C, point mutations and WAPL rescue (NIPBL); SEC/MS/Co-IP (ASXL3); conditional KO and ChIP-seq (CD8 T cells); ChIP/Co-IP (FXR, CEBPD)

    PMID:32669118 PMID:33290278 PMID:33768129 PMID:34037670 PMID:34611363 PMID:34754068 PMID:36475791 PMID:37737256

    Open questions at the time
    • How dimerization, methylation, and condensation are coordinated is unresolved
    • Structural basis of the NIPBL and ASXL3 (ET-domain BBM) interactions partially defined
  11. 2022 High

    Resolved that BRD4 promotes HR-directed DSB repair biochemically via SWI/SNF, independent of transcription, and that JNK phosphorylation toggles its HAT versus kinase activities, separating its enzymatic states.

    Evidence Cell-free Xenopus extract reconstitution and immunodepletion (HR/SWI/SNF); in vitro kinase/HAT assays with phospho-mutants and JNK modulation (activity switch)

    PMID:35641523 PMID:39454579

    Open questions at the time
    • Whether the kinase/HAT switch operates at endogenous physiological stoichiometry in vivo unclear
    • Direct SWI/SNF contact interface on BRD4 not mapped
  12. 2023 High

    Showed bromodomains are dispensable for Pol II pause release, isolating the CTM–P-TEFb module as the necessary and sufficient elongation effector, and refined the chromatin-versus-self-assembly logic of condensate nucleation.

    Evidence Degron depletion with domain-deletion complementation and PRO-seq/ChIP-seq (CTM); live imaging, FRAP, chromatin-binding mutants and simulations (condensate nucleation)

    PMID:37442129 PMID:38656803

    Open questions at the time
    • How the bromodomain-dependent and bromodomain-independent BRD4 pools are partitioned in cells unknown
    • In vivo relevance of off-chromatin condensation thresholds untested
  13. 2024 Medium

    Extended BRD4 function to histone lactylation, linking it to H4K8la deposition and astrocyte polarization in injury, suggesting broader histone-acylation reader/effector roles.

    Evidence BRD4 siRNA in vitro/in vivo, H4K8la western/immunofluorescence, astrocyte polarization in a murine subarachnoid hemorrhage model

    PMID:39080649

    Open questions at the time
    • Whether BRD4 directly recognizes or enzymatically promotes lactylation not established
    • Mechanism connecting BRD4 to A1 polarization undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural and catalytic basis of BRD4's intrinsic kinase and HAT activities, and how its enzymatic, dimerization, methylation, and phase-separation states are integrated to select genomic targets, remain unresolved.
  • No reported structure of the BRD4 kinase or HAT catalytic module
  • Interplay among PTMs, dimerization, and condensation in target selection not mechanistically integrated
  • Determinants of activator versus repressor behavior at individual loci unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0042393 histone binding 3 GO:0060090 molecular adaptor activity 3 GO:0140110 transcription regulator activity 3 GO:0016740 transferase activity 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0003677 DNA binding 1
Localization
GO:0005634 nucleus 3 GO:0000228 nuclear chromosome 2 GO:0005654 nucleoplasm 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-4839726 Chromatin organization 3 R-HSA-73894 DNA Repair 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-162582 Signal Transduction 2 R-HSA-1640170 Cell Cycle 2
Partners
ASXL3CDC6CDK9CEBPDHSF1IRF1MTHFD1NIPBL
Complex memberships
MediatorP-TEFb elongation complexSWI/SNFcondensin II

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 BRD4 (MCAP) associates with mitotic chromosomes during cell division, remaining chromosome-bound while most nuclear regulatory factors are released into the cytoplasm. Microinjection of anti-BRD4 antibody into HeLa cell nuclei completely inhibited entry into mitosis without abrogating ongoing DNA replication, establishing a role in G2/M transition. Immunofluorescence/live-cell imaging, microinjection of neutralizing antibody, cell cycle analysis Molecular and cellular biology High 10938129
2007 BRD4 binds to acetylated chromatin via its double bromodomains and is found in transcription complexes including Mediator and P-TEFb elongation factor, stimulating HIV-1 transcription in a Tat-independent manner. BRD4 also serves as a cellular adaptor for papillomavirus E2 protein, tethering viral genomes to mitotic chromosomes to facilitate viral genome segregation during mitosis. Co-immunoprecipitation, transcriptional reporter assays, biochemical fractionation The Journal of biological chemistry Medium 17329240
2013 A specific isoform of BRD4 functions as an endogenous inhibitor of DNA damage response signaling by recruiting the condensin II chromatin remodeling complex to acetylated histones via bromodomain interactions. Loss of this isoform results in relaxed chromatin, rapid checkpoint recovery and enhanced survival after irradiation; gain of function compacted chromatin and attenuated DNA damage signaling. High-content multiplex RNAi screen, loss-of-function and gain-of-function experiments, chromatin compaction assays, irradiation survival assays Nature High 23728299
2015 BRD4 can be recruited to the E3 ubiquitin ligase cereblon via a PROTAC (ARV-825), leading to ubiquitin-mediated proteasomal degradation of BRD4. BRD4 inhibition (without degradation) leads to robust BRD4 protein accumulation, whereas degradation more effectively suppresses c-MYC levels and downstream signaling. PROTAC-mediated targeted protein degradation, western blot, cell viability and apoptosis assays Chemistry & biology High 26051217
2016 BRD4 and DOT1L exist in separate native protein complexes. DOT1L-mediated H3K79 dimethylation facilitates histone H4 acetylation, which in turn regulates BRD4 binding to chromatin. Genetic or pharmacological disruption of BRD4 and DOT1L showed synergistic activity against MLL leukemia, establishing a functional collaboration at highly transcribed genes near super-enhancers. Quantitative proteomics, chemoproteomics, biochemical fractionation, genetic disruption, small-molecule inhibition, ChIP-seq Nature structural & molecular biology High 27294782
2016 BRD4 interacts with the heat shock factor 1 (HSF1) and, under heat stress, is recruited to nuclear stress bodies where it regulates splicing. BRD4 depletion causes increased intron retention and reduced mRNA abundance of affected transcripts during heat stress. RNA-seq, co-immunoprecipitation, immunofluorescence, BRD4 knockdown Nucleic acids research Medium 27536004
2016 BRD4 phosphorylation by CK2 and dephosphorylation by PP2A modulates its chromatin targeting, transcription factor recruitment, and function in cancer progression. Phosphorylation status is also critical for papillomavirus E1/E2-dependent replication and viral gene transcription. Phosphorylation/dephosphorylation assays, functional transcriptional and replication assays, pharmacological modulation of CK2/PP2A Drug discovery today. Technologies Medium 27769352
2017 BRD4 acts as a transcriptional repressor of autophagy and lysosomal function genes via binding to the histone methyltransferase G9a/EHMT2. During starvation, AMPK and SIRT1 displace chromatin-bound BRD4 to instigate autophagy gene activation. The BRD4-NUT fusion oncoprotein also blocks autophagy and lysosome function. BRD4 knockdown, in vitro and in vivo autophagy assays, ChIP, co-immunoprecipitation, AMPK/SIRT1 pathway manipulation Molecular cell High 28525743
2017 BRD4 is required for myogenic differentiation, with preferential binding to the Myog promoter coinciding with increased H3K27 acetylation during C2C12 myoblast differentiation, whereas BRD3 downregulation enhances differentiation, establishing distinct and opposing roles for BRD4 and BRD3 in skeletal myogenesis. RNA interference knockdown of individual BET proteins, ChIP for BRD4 at Myog promoter, BET inhibitor treatment, myogenic differentiation assays Scientific reports Medium 28733670
2018 BRD4 associates with and regulates the function of pre-replication factor CDC6 and plays an indispensable role in DNA replication checkpoint signaling. BRD4 inhibition causes rapid reduction in CHK1 phosphorylation and aberrant DNA replication re-initiation. Co-immunoprecipitation, BRD4 inhibition with JQ1/AZD5153, CHK1 phosphorylation assays, DNA replication assays, in vivo xenograft models Oncogene Medium 29636547
2019 BRD4 interacts directly with MTHFD1 (a folate pathway enzyme) in the nucleus, recruiting it to specific genomic loci. Inhibition of either BRD4 or MTHFD1 produces similar changes in nuclear metabolite composition and gene expression, establishing a direct link between folate metabolism and BRD4-dependent transcriptional regulation. Genetic and physical interaction screens, nuclear fractionation, ChIP-seq, co-immunoprecipitation, metabolomics Nature genetics High 31133746
2019 BRD4 functions as an effector of TGF-β signaling in cardiac fibroblasts, undergoing stimulus-dependent genome-wide redistribution and becoming enriched on a subset of enhancers and super-enhancers. Dynamic chromatin targeting of BRD4 is controlled in part by p38 MAPK and drives RNA polymerase II activation and fibrogenic gene expression. RNA-seq, mass spectrometry, ChIP-seq, BRD4 inhibition (JQ1), TGF-β stimulation, primary adult fibroblasts and in vivo mouse model Circulation research High 31409188
2019 BRD4 is required for hematopoietic stem cell expansion and progenitor development in conditional knockout mice. Despite broadly occupying the macrophage genome and participating in super-enhancer formation, BRD4 is not required for macrophage super-enhancers or inflammatory LPS responses, as knockout macrophages form compensatory BRD4-less super-enhancers. Conditional knockout mice (Brd4 KO), ChIP-seq, transcriptome analysis, LPS stimulation The EMBO journal High 30842097
2019 BRD4 regulates necroptosis by promoting transcription of MLKL. BRD4, IRF1, P-TEFb, and RNA polymerase II form a transcription complex at the MLKL locus, and BET inhibitors interfere with this complex formation, downregulating MLKL expression and protecting cells from necroptosis. Cell-based small-molecule screen, Co-immunoprecipitation of transcription complex components, MLKL expression analysis, necroptosis assays Cell death and differentiation Medium 30644439
2019 BRD4 and P300 are sufficient to trigger genome-wide transcriptional competency during zygotic genome activation in zebrafish. Inhibition of histone acetylation blocks genome activation, establishing that P300 and BRD4 regulate this process through histone acetylation. Live imaging of transcription, maternal mRNA translation block, P300/BRD4 ectopic expression, histone acetylation inhibition, zebrafish embryo model Developmental cell High 31211993
2020 BRD4 short isoform (BRD4-S) forms nuclear condensates with liquid-like properties that colocalize with BRD4L, MED1, and H3K27ac sites. BRD4-S condensation is mediated by intrinsically disordered regions and bromodomain binding to DNA and acetylated chromatin, and BRD4-S phosphorylation diminishes condensate formation. Live-cell imaging, fluorescence recovery after photobleaching (FRAP), isoform-specific knockdown, ectopic expression, ChIP-seq, CUT&RUN Nature structural & molecular biology High 32203489
2020 BRD4 phosphorylates MYC at Thr58, leading to MYC ubiquitination and degradation. BRD4 degradation (but not inhibition) results in increased MYC protein levels. MYC inhibits BRD4's histone acetyltransferase (HAT) activity. ERK1 regulates MYC levels both directly and indirectly by inhibiting BRD4 kinase activity. In vitro kinase assay, phospho-specific antibodies, ubiquitination assays, BRD4 degradation vs. inhibition comparison, HAT activity assays Proceedings of the National Academy of Sciences of the United States of America High 32482868
2020 BRD4 inhibits CSF1 expression through suppressing HIF1α, thereby reducing macrophage colony-stimulating factor secretion by tumor cells and blocking proliferation of tumor-associated macrophages. BRD4 inhibitor treatment, gene expression analysis, cytokine secretion assays, xenograft and syngeneic tumor models Nature communications Medium 32286255
2020 BRD4 loss of function causes RNA polymerase II pausing on chromatin, leading to accumulation of R-loops (RNA:DNA hybrids) at BRD4 occupancy sites in S-phase cells, resulting in transcription-replication conflicts and DNA damage. The BRD4 C-terminal domain interacting with P-TEFb is required to prevent R-loop formation. BET protein LOF experiments, RNAPII ChIP-seq, R-loop detection (DRIP-seq), DNA damage assays, domain deletion mutants Cell reports High 32966794
2020 The BRD4 long isoform (BRD4-L) is tumor-suppressive while the BRD4 short isoform (BRD4-S) is oncogenic in breast cancer cell proliferation, migration, and mammary tumor formation. BRD4-S and EN1 comodulate the extracellular matrix-associated matrisome network via enhancer regulation. Isoform-specific knockdown, endogenous protein detection, transgene expression, RNA-seq, ChIP-seq, CUT&RUN, mouse tumor models Molecular cell High 32446320
2020 ASXL3 directly interacts with BRD4's extra-terminal (ET) domain via a novel BRD4 binding motif (BBM), functioning as an adaptor protein that maintains BRD4 chromatin occupancy at active enhancers. Genetic depletion of ASXL3 reduces genome-wide H3K27ac levels and BRD4-dependent gene expression in SCLC. Size exclusion chromatography, mass spectrometry, western blot, Co-IP, ChIP-seq, RNA-seq, ASXL3 depletion Genome medicine High 32669118
2021 BRD4 interacts with NIPBL (a cohesin agonist) and BRD4 depletion reduces NIPBL chromatin occupancy, suggesting BRD4 stabilizes NIPBL on chromatin. BRD4 depletion compromises genome folding and loop extrusion, and individual amino acid mutations disrupting the BRD4-NIPBL interaction impede neural crest differentiation into smooth muscle. Co-immunoprecipitation, ChIP-seq, chromatin interaction mapping (Hi-C), imaging, point mutation analysis, conditional Brd4 knockout in neural crest, WAPL loss rescue experiment Nature genetics High 34611363
2021 BRD4 chromatin-bound and promoter-associated forms have mutually exclusive activities: chromatin-bound BRD4 mediates histone acetyltransferase (HAT) activity for chromatin remodeling, while promoter-associated BRD4 mediates kinase activity for transcription. JNK-mediated phosphorylation at Thr1186 and Thr1212 triggers transient BRD4 release from chromatin, disrupting HAT activity and potentiating kinase activity toward RNA Pol II, PTEFb, and c-Myc. In vitro kinase and HAT activity assays, phospho-specific antibodies, JNK inhibition and stimulation, functional assays (CD8 expression, EMT) Molecular cell High 39454579
2021 BRD4 is required for differentiation and maintenance of terminally fated effector CD8 T cells during infection. BRD4 binds diverse regulatory regions critical to effector T cell differentiation and controls transcriptional activity of terminal effector-specific super-enhancers in vivo. Induced deletion of Brd4 impaired terminal effector T cell phenotype maintenance. Small-molecule inhibition, RNAi, induced genetic deletion (Brd4 conditional KO), ChIP-seq, in vivo infection models, tumor microenvironment models The Journal of experimental medicine High 34037670
2021 BRD4 phosphorylation by CK2 modulates BRD4 dimerization. Two conserved regions, a coiled-coil motif and the BID (Basic-residue enriched Interaction Domain), form the phosphorylation-dependent dimerization domain (PDD). Bivalent inhibitors induce a conformational change within BRD4 dimers in vitro and in cancer cells. Integrative structural biology, biophysical analysis, in vitro CK2 phosphorylation, domain mutagenesis, bivalent inhibitor studies in cells Communications biology High 34754068
2021 BRD4 is required for FXR-mediated regulation of bile acid homeostasis genes (including SHP and CYP7A1). Liver-specific downregulation of BRD4 disrupts bile acid homeostasis. FXR-activated corepressor SMRT decreases NF-κB binding at inflammatory genes in a BRD4-dependent manner. Liver-specific Brd4 knockdown in mice, gene expression analysis, ChIP, Co-immunoprecipitation of FXR-SMRT-BRD4 complexes JCI insight Medium 33290278
2022 BRD4 promotes DNA double-strand break resection and homologous recombination via interactions with the SWI/SNF chromatin remodeling complex and resection machinery, as established in a cell-free Xenopus egg extract system, independent of gene expression effects. Cell-free Xenopus egg extract reconstitution, biochemical DSB repair assays, BRD4 immunodepletion, SWI/SNF interaction assays Nature communications High 35641523
2022 PRMT2 and PRMT4 methylate BRD4 at R179, R181, and R183, and this arginine methylation selectively promotes BRD4 recruitment to acetylated histones/chromatin for transcriptional regulation and DNA repair. DNA damage induces BRD4 arginine methylation, promoting its chromatin binding for DNA repair. BRD4 arginine methylation deficiency suppresses tumor growth. In vitro methylation assays, Co-IP, ChIP-seq, arginine-to-lysine point mutants, DNA damage assays, tumor growth assays Science advances High 36475791
2022 PRMT1 asymmetrically methylates BRD4 at R179/181/183 (the same sites also targeted by PRMT2/4), and PRMT1-mediated methylation promotes BRD4 phosphorylation. JMJD6 demethylase antagonizes this methylation. BRD4 R179/181/183K mutant cells show reduced ovarian cancer metastasis. In vitro methylation assays, Co-IP, phosphorylation analysis, arginine-to-lysine mutant expression, in vivo and in vitro invasion assays Cell death & disease Medium 37737256
2022 BRD4 bromodomains are dispensable for RNA polymerase II pause release. A minimal, bromodomain-less 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, indicating a distinct bromodomain-independent BRD4-PTEFb population regulates transcription. Rapid protein depletion (degron system), genetic complementation with domain deletion mutants, nascent transcription analysis (PRO-seq), ChIP-seq Molecular cell High 37442129
2023 BRD4 transcriptional condensate formation is regulated by interplay between chromatin binding and self-assembly: BRD4-chromatin interactions control condensate nucleation rate and multivalent acetylated chromatin sites provide a platform for BRD4 clustering below concentrations required for off-chromatin condensation, providing a mechanism for selective condensate formation at acetylated chromatin regions. Live-cell imaging, coarse-grained simulations, BRD4 chromatin-binding mutant analysis, FRAP Molecular biology of the cell Medium 38656803
2024 BRD4 plays a role in histone lactylation (H4K8la) in astrocytes. Targeted silencing of BRD4 in astrocytes significantly reduces H4K8la lactylation, aggravating A1 astrocyte polarization after subarachnoid hemorrhage, affecting neural function recovery. BRD4 siRNA silencing in vitro and in vivo, H4K8la western blot and immunofluorescence, astrocyte polarization assays, murine SAH model Journal of neuroinflammation Medium 39080649
2021 BRD4/CEBPD relationship: BRD4 (specifically its bromodomain-1) controls CEBPD expression via enhancer regulation. Endogenous BRD4 protein co-immunoprecipitates with CEBPD, and both proteins co-precipitate the Cebpd promoter and enhancer DNA, forming a BRD4/CEBPD/promoter/enhancer complex that mediates TNF-α-induced SMC inflammation via PDGFRα. ChIP-seq, Co-IP, BRD4 gene silencing, bromodomain-1 vs. -2 domain mutants, enhancer deletion, gain- and loss-of-function experiments Molecular therapy. Methods & clinical development Medium 33768129

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 892 26051217
2018 BRD4 and Cancer: going beyond transcriptional regulation. Molecular cancer 588 30466442
2007 The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation. The Journal of biological chemistry 558 17329240
2013 The bromodomain protein Brd4 insulates chromatin from DNA damage signalling. Nature 269 23728299
2020 Antibody-PROTAC Conjugates Enable HER2-Dependent Targeted Protein Degradation of BRD4. ACS chemical biology 256 32338867
2000 A bromodomain protein, MCAP, associates with mitotic chromosomes and affects G(2)-to-M transition. Molecular and cellular biology 253 10938129
2017 Bromodomain Protein BRD4 Is a Transcriptional Repressor of Autophagy and Lysosomal Function. Molecular cell 209 28525743
2019 Dynamic Chromatin Targeting of BRD4 Stimulates Cardiac Fibroblast Activation. Circulation research 155 31409188
2020 Potent BRD4 inhibitor suppresses cancer cell-macrophage interaction. Nature communications 145 32286255
2018 BET Family Protein BRD4: An Emerging Actor in NFκB Signaling in Inflammation and Cancer. Biomedicines 145 29415456
2020 Opposing Functions of BRD4 Isoforms in Breast Cancer. Molecular cell 141 32446320
2020 Roles of the BRD4 short isoform in phase separation and active gene transcription. Nature structural & molecular biology 135 32203489
2020 MYC protein stability is negatively regulated by BRD4. Proceedings of the National Academy of Sciences of the United States of America 127 32482868
2018 Targeting Brd4 for cancer therapy: inhibitors and degraders. MedChemComm 126 30542529
2013 Megalencephaly syndromes and activating mutations in the PI3K-AKT pathway: MPPH and MCAP. American journal of medical genetics. Part C, Seminars in medical genetics 124 23592320
2021 Autophagy enhanced by curcumin ameliorates inflammation in atherogenesis via the TFEB-P300-BRD4 axis. Acta pharmaceutica Sinica. B 112 35646539
2019 BRD4 directs hematopoietic stem cell development and modulates macrophage inflammatory responses. The EMBO journal 111 30842097
2019 Brd4 and P300 Confer Transcriptional Competency during Zygotic Genome Activation. Developmental cell 109 31211993
2019 Emerging roles of and therapeutic strategies targeting BRD4 in cancer. Cellular immunology 108 30832981
2014 The bromodomain protein BRD4 regulates the KEAP1/NRF2-dependent oxidative stress response. Cell death & disease 101 24763052
2016 Functional interdependence of BRD4 and DOT1L in MLL leukemia. Nature structural & molecular biology 92 27294782
2018 BRD4 facilitates replication stress-induced DNA damage response. Oncogene 81 29636547
2020 BRD4 Prevents R-Loop Formation and Transcription-Replication Conflicts by Ensuring Efficient Transcription Elongation. Cell reports 80 32966794
2012 Two faces of brd4: mitotic bookmark and transcriptional lynchpin. Transcription 77 23131666
2022 Regulation of programmed cell death by Brd4. Cell death & disease 75 36539410
2023 Super-enhancers and the super-enhancer reader BRD4: tumorigenic factors and therapeutic targets. Cell death discovery 72 38135679
2021 Supercharging BRD4 with NUT in carcinoma. Oncogene 71 33452461
2019 MTHFD1 interaction with BRD4 links folate metabolism to transcriptional regulation. Nature genetics 71 31133746
2021 BRD4 orchestrates genome folding to promote neural crest differentiation. Nature genetics 69 34611363
2015 BRD4 Structure-Activity Relationships of Dual PLK1 Kinase/BRD4 Bromodomain Inhibitor BI-2536. ACS medicinal chemistry letters 69 26191363
2020 Targeting BRD4 prevents acute gouty arthritis by regulating pyroptosis. International journal of biological sciences 66 33162822
2014 Brd4 and HEXIM1: multiple roles in P-TEFb regulation and cancer. BioMed research international 66 24592384
2017 Inhibition of BRD4 Suppresses Cell Proliferation and Induces Apoptosis in Renal Cell Carcinoma. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 62 28391274
2014 BRD4 regulates Nanog expression in mouse embryonic stem cells and preimplantation embryos. Cell death and differentiation 61 25146928
2020 Brd4-p300 inhibition downregulates Nox4 and accelerates lung fibrosis resolution in aged mice. JCI insight 60 32544088
2020 Novel strategies targeting bromodomain-containing protein 4 (BRD4) for cancer drug discovery. European journal of medicinal chemistry 58 32502863
2022 BRD4 and MYC: power couple in transcription and disease. The FEBS journal 57 35866356
2021 BRD4 in physiology and pathology: ''BET'' on its partners. BioEssays : news and reviews in molecular, cellular and developmental biology 55 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
2023 BRD4-targeting PROTAC as a unique tool to study biomolecular condensates. Cell discovery 51 37156794
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
2021 BRD4 inhibition sensitizes cervical cancer to radiotherapy by attenuating DNA repair. Oncogene 49 33712705
2017 BRD4 inhibition for the treatment of pathological organ fibrosis. F1000Research 49 28721198
2023 Distinct layers of BRD4-PTEFb reveal bromodomain-independent function in transcriptional regulation. Molecular cell 47 37442129
2019 A patent review of BRD4 inhibitors (2013-2019). Expert opinion on therapeutic patents 47 31815566
2016 Phospho-BRD4: transcription plasticity and drug targeting. Drug discovery today. Technologies 47 27769352
2016 Involvement of Brd4 in different steps of the papillomavirus life cycle. Virus research 46 27965149
2024 Lactylation of histone by BRD4 regulates astrocyte polarization after experimental subarachnoid hemorrhage. Journal of neuroinflammation 45 39080649
2018 Pluripotency transcription factors and Tet1/2 maintain Brd4-independent stem cell identity. Nature cell biology 45 29662175
2004 Brd4: tethering, segregation and beyond. Trends in microbiology 45 15539109
2015 Targeting bromodomain-containing protein 4 (BRD4) benefits rheumatoid arthritis. Immunology letters 44 26093279
2022 BRD4 promotes resection and homology-directed repair of DNA double-strand breaks. Nature communications 43 35641523
2022 BRD4: a general regulator of transcription elongation. Transcription 43 36047906
2022 BRD4 Inhibition Attenuates Inflammatory Pain by Ameliorating NLRP3 Inflammasome-Induced Pyroptosis. Frontiers in immunology 42 35154163
2021 BRD4: An emerging prospective therapeutic target in glioma. Molecular therapy oncolytics 42 33851008
2022 Post-Translational Modifications of BRD4: Therapeutic Targets for Tumor. Frontiers in oncology 41 35402244
2023 Brd4 proteolysis-targeting chimera nanoparticles sensitized colorectal cancer chemotherapy. Journal of controlled release : official journal of the Controlled Release Society 40 36538950
2022 Arginine methylation of BRD4 by PRMT2/4 governs transcription and DNA repair. Science advances 40 36475791
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
2018 Dual BRD4 and AURKA Inhibition Is Synergistic against MYCN-Amplified and Nonamplified Neuroblastoma. Neoplasia (New York, N.Y.) 38 30153557
2024 Cotargeting CDK4/6 and BRD4 Promotes Senescence and Ferroptosis Sensitivity in Cancer. Cancer research 37 38277141
2017 BRD3 and BRD4 BET Bromodomain Proteins Differentially Regulate Skeletal Myogenesis. Scientific reports 37 28733670
2017 BRD4 inhibitors block telomere elongation. Nucleic acids research 37 28854735
2023 The BRD4-NUT Fusion Alone Drives Malignant Transformation of NUT Carcinoma. Cancer research 35 37819236
2020 The therapeutic potential of BRD4 in cardiovascular disease. Hypertension research : official journal of the Japanese Society of Hypertension 33 32409773
2019 The bromodomain protein BRD4 positively regulates necroptosis via modulating MLKL expression. Cell death and differentiation 32 30644439
2017 BRD4 is a newly characterized transcriptional regulator that represses autophagy and lysosomal function. Autophagy 32 28837371
2021 MED12 and BRD4 cooperate to sustain cancer growth upon loss of mediator kinase. Molecular cell 31 34910943
2021 Bromodomain protein BRD4 directs and sustains CD8 T cell differentiation during infection. The Journal of experimental medicine 30 34037670
2021 Dual-target inhibitors of bromodomain-containing protein 4 (BRD4) in cancer therapy: Current situation and future directions. Drug discovery today 30 34438075
2021 BRD4 drives esophageal squamous cell carcinoma growth by promoting RCC2 expression. Oncogene 30 34750516
2015 BRD4 promotes pancreatic ductal adenocarcinoma cell proliferation and enhances gemcitabine resistance. Oncology reports 30 25647019
2024 Interplay of condensation and chromatin binding underlies BRD4 targeting. Molecular biology of the cell 28 38656803
2023 YAP/BRD4-controlled ROR1 promotes tumor-initiating cells and hyperproliferation in pancreatic cancer. The EMBO journal 28 37096681
2020 BRD4 inhibition and FXR activation, individually beneficial in cholestasis, are antagonistic in combination. JCI insight 27 33290278
2019 B7-H3 is regulated by BRD4 and promotes TLR4 expression in pancreatic ductal adenocarcinoma. The international journal of biochemistry & cell biology 27 30664982
2017 BRD4 promotes p63 and GRHL3 expression downstream of FOXO in mammary epithelial cells. Nucleic acids research 27 27980063
2023 Methylation of BRD4 by PRMT1 regulates BRD4 phosphorylation and promotes ovarian cancer invasion. Cell death & disease 26 37737256
2020 ARV-825-induced BRD4 protein degradation as a therapy for thyroid carcinoma. Aging 26 32163373
2024 Exploration of the tunability of BRD4 degradation by DCAF16 trans-labelling covalent glues. European journal of medicinal chemistry 25 39341093
2022 Therapeutic Targeting of EZH2 and BET BRD4 in Pediatric Rhabdoid Tumors. Molecular cancer therapeutics 24 35247919
2021 Modulation of BRD4 in HIV epigenetic regulation: implications for finding an HIV cure. Retrovirology 24 33413475
2022 Targeting CDCP1 gene transcription coactivated by BRD4 and CBP/p300 in castration-resistant prostate cancer. Oncogene 23 35513563
2021 A hierarchical and collaborative BRD4/CEBPD partnership governs vascular smooth muscle cell inflammation. Molecular therapy. Methods & clinical development 23 33768129
2021 Phosphorylation-dependent BRD4 dimerization and implications for therapeutic inhibition of BET family proteins. Communications biology 22 34754068
2020 RSV Reprograms the CDK9•BRD4 Chromatin Remodeling Complex to Couple Innate Inflammation to Airway Remodeling. Viruses 22 32331282
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
2021 A natural product targets BRD4 to inhibit phase separation and gene transcription. iScience 21 35072011
2024 An updated patent review of BRD4 degraders. Expert opinion on therapeutic patents 20 39219068
2023 BRD4 Regulates Glycolysis-Dependent Nos2 Expression in Macrophages Upon H pylori Infection. Cellular and molecular gastroenterology and hepatology 20 37820788
2024 A BRD4-Targeting Photothermal Agent for Controlled Protein Degradation. Angewandte Chemie (International ed. in English) 19 38721770
2024 BRD4: an effective target for organ fibrosis. Biomarker research 19 39215370
2024 Phosphorylation by JNK switches BRD4 functions. Molecular cell 19 39454579
2020 Development of small-molecule BRD4 degraders based on pyrrolopyridone derivative. Bioorganic chemistry 19 32361153
2024 BRD4 degraders may effectively counteract therapeutic resistance of leukemic stem cells in AML and ALL. American journal of hematology 18 38822666
2022 Bromodomain Protein BRD4-Mediated Mutant p53 Transcription Promotes TNBC Progression. International journal of molecular sciences 18 36499487
2022 Design, synthesis, and biological evaluation of BRD4 degraders. Bioorganic & medicinal chemistry 18 36563515

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