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FLASH GENE
Symbol BRD4 contributors: mct/pgu - updated : 29-12-2017
HGNC name bromodomain containing 4
HGNC id 13575
EXPRESSION
Type ubiquitous
   expressed in (based on citations)
organ(s)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
Digestiveintestinelarge intestinecolon moderately
 liver   moderately
Lymphoid/Immunelymph node   predominantly
 thymus   highly
Reproductivefemale systemovary  moderately
 female systemplacenta  moderately
Respiratorylung   moderately
 respiratory tractlarynx  moderately
cell lineage
cell lines
fluid/secretion blood
at STAGE
physiological period pregnancy
cell cycle     cell cycle, checkpoint, G2M
Text placenta
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • eight regions with homology to kinase subdomain motifs scattered across its N-terminal region
  • two bromodomains, binding to acetylated lysine-310 (Huang 2009)(inhibitor JQ1 binds to the Kac binding site of BET bromodomains)
  • an BET domain,
  • a serine-rich region
  • C-terminal domain (CTD) that interacts with CDK9
  • extraterminal (ET) domain, interacting with WHSC1L1, JMJD6, CHD4, GLTSCR1, and ATAD5
  • conjugated PhosphoP
    HOMOLOGY
    interspecies homolog to rattus Brd4 (96.1pc)
    homolog to murine Brd4 (95.7pc)
    intraspecies homolog to RING3
    paralog to BRD3 (54 p100)
    Homologene
    FAMILY
  • BET subgroup of the bromodomain superfamily
  • RING finger proteins family
  • CATEGORY regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,nucleus,nucleoplasm
    intracellular,nucleus,chromatin/chromosome
    text
  • dividing cells
  • associated with chromosomes during mitosis
  • basic FUNCTION
  • playing a role in a process governing chromosomal dynamics during mitosis
  • regulating cell cycle progression in part by interacting with RFC
  • chromatin adapter that maintains epigenetic memory and regulates cell cycle progression
  • structural scaffold that regulates transcription indirectly by recruiting the elongation factor, CDK9, to the transcription preinitiation complex
  • capable of interacting with acetylated histones, and implicated in transmitting epigenetic memory through mitosis
  • recruits CDK9 to phosphorylate C-terminal domain of RNA polymerase II and facilitate the transcription of NF-kappaB-dependent inflammatory genes
  • functions as an associated factor and positive regulator of CCNT1, a CDK9-cyclin T1 heterodimer that stimulates transcriptional elongation by phosphorylating RNA polymerase II
  • critical mediator of transcriptional elongation, functioning to recruit the positive transcription elongation factor complex
  • is essential for the maintenance of the cell cycle progression mediated at least in part through the control of transcription of AURKB cell cycle regulatory gene
  • coactivator of NFKappaB through binding to acetylated RELA
  • regulating HIV transcription through phosphorylation of CDK9
  • BET family proteins recognize acetylated chromatin through their two bromodomains, acting as transcriptional activators or tethering viral genomes to the mitotic chromosomes of their host
  • plays critical roles in development, cancer progression, and virus-host pathogenesis
  • clearly gains a histone acetylation function through fusion with the NUT protein, which recruits HATs
  • contributes to regulation of both cell cycle and transcription of oncogenes, HIV, and human papilloma virus (HPV)
  • is a regulator of eukaryotic transcription
  • is an atypical protein kinase that exhibits both auto- and transphosphorylation
  • is a CTD Ser2 kinase that is distinct from CDK9 in its substrate specificity
  • coordinates both positive and negative regulation of IFN-stimulated genes (ISGs) elongation
  • previously known for its role in transcriptional control, is an insulator of chromatin that can modulate the signalling response to DNA damage
  • plays an important role in embryonic stem cell (ESC) regulation
  • is epigenetically regulated during hematopoietic differentiation ESCs in the context of a still unknown signaling pathway
  • is a signal transducer of the cellular response to oxidative stress
  • activates CDK9 for RNA polymerase II CTD phosphorylation
  • serves as a chromatin platform required for the recruitment of repair components during Class switch recombination (CSR) and general DNA damage
  • is a central regulator of ESR1 function and potential therapeutic target
  • involved in multiple steps of the transcription hierarchy, primarily by facilitating transcript elongation both at enhancers and on gene bodies independently of CDK9
  • prominent transcriptional role for BRD4, suggesting a possible removal mechanism for chromatin components from the genome via the progressing acrosome as transcription is repressed and chromatin is compacted during spermiogenesis
  • can act as a global genomic regulator to direct the fibrotic response through its coordinated regulation of myofibroblast transcription
  • separate and interdependent BRD2 and BRD4 functions in potentiating the genetic program required for Th17 cell development and adaptive immunity
  • BRD4 is essential for the repair of DNA double-strand breaks (DSBs) and mediates the formation of oncogenic gene rearrangements by engaging the non-homologous end joining (NHEJ) pathway
  • BRD4 is a central regulator of the pro-fibrotic cardiac fibroblast phenotype, with a MAPK14-dependent signaling circuit for epigenetic reprogramming in heart failure (HF)
  • CELLULAR PROCESS cell cycle, division, mitosis
    cell cycle, checkpoint
    cell cycle, progression
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
  • binding to euchromatin
  • binding to chromosomes during mitosis
  • RNA
    small molecule
    protein
  • RFC
  • BRD-NUT fusion proteins contribute to carcinogenesis by associating with chromatin and interfering with epithelial differentiation
  • CDK9 nuclear localization and activation depends on BRD4, which is also known to interact with a variety of other factors, including the mediator complex
  • binding to acetylated lysine-310 of RELA
  • interacting with CCNT1 (recruitment by BRD4 to chromosomes at late mitosis may indicate those genes whose active transcription status must be preserved across cell division)
  • key interacting partner of papillomavirus E2 protein, stabilizing the protein and preventing its ubiquitylation
  • recruits CCNT1 to mitotic chromosomes resulting in increased expression of growth-promoting genes
  • binds to acetylated chromatin through its bromodomains and becomes associated with both interphase chromatin and mitotic chromosomes
  • BRD4-NUT oncogene perturbs BRD4 functions to block cellular differentiation and to contribute to the oncogenic progression in the highly aggressive NUT midline carcinoma
  • atypical kinase that binds to the C-terminal domain (CTD) of RNA polymerase II and directly phosphorylates its serine 2 (Ser2) sites under conditions where other CTD kinases are inactive
  • regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells
  • interactions of both JMJD6 and BRD4 with the CDK9 complex permit its activation and pause release of regulated coding genes
  • BRD4 directly targeting the HMOX1 promoter over the SP1-binding sites
  • AML maintenance function of BRD4 requires its interaction with WHSC1L1, which belongs to a subfamily of H3K36 methyltransferases
  • cell & other
    REGULATION
    inhibited by JQ1, a selective and potent inhibitor of BET family bromodomains
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral   translocation    
    translocated t(15;19) (q13;p13.1) in upper respiratory tract carcinoma (fusion with NUT), highly lethal carcinoma
    tumoral   translocation    
    t(14;19)(q32;p13), recurrent translocation in B cell malignancies, fusion of Ig heavy-chain (IGH@)-variable region with BRD4
    tumoral        
    BRD4 activation in breast carcinomas induces a gene expression profile predictive of breast cancer outcome
    tumoral     --other  
    aberrant expression of BRD4 in thyroid cancer is possibly involved in tumor progression
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerhemopathy 
    inhibition of BRD4 is a promising therapeutic strategy in AML (acute myeloid leukaemia) and, potentially, other cancers
    cancerhemopathy 
    small molecule inhibitor of BRD4, has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis
    cancerdigestiveliver
    is a potential novel target for the development of therapeutic approaches against HCC
    ANIMAL & CELL MODELS
  • Brd4-depleted mice display reversible epidermal hyperplasia, alopecia, and decreased cellular diversity and stem cell depletion in the small intestine