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FLASH GENE
Symbol BRD4 contributors: mct/pgu - updated : 29-12-2017
HGNC name bromodomain containing 4
HGNC id 13575
Location 19p13.12      Physical location : 15.348.301 - 15.391.262
Synonym name
  • mitotic chromosome associated protein
  • chromosome-associated protein
  • bromodomain and extraterminal (BET) protein
  • Synonym symbol(s) MCAP, HUNKI, CAP, HUNK1
    DNA
    TYPE functioning gene
    STRUCTURE 42.96 kb     20 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    Physical map
    LOC390892 19 similar to Olfactory receptor 7A10 (OST027) LOC390893 19 similar to Olfactory receptor 7A10 (OST027) LOC390894 19 similar to Olfactory receptor 7A2 OR7A17 19p13.13 olfactory receptor, family 7, subfamily A, member 17 OR7A18P 19p13.13 olfactory receptor, family 7, subfamily A, member 18 pseudogene LOC390895 19 similar to olfactory receptor, family 7, subfamily A, member 17 OR7A14P 19p13.1 olfactory receptor, family 7, subfamily A, member 14 pseudogene OR7A11P 19p13.1 olfactory receptor, family 7, subfamily A, member 11 pseudogene OR7A15P 19p13.1 olfactory receptor, family 7, subfamily A, member 15 pseudogene OR7C2 19p13.1 olfactory receptor, family 7, subfamily C, member 2 SLC1A6 19p13.11 solute carrier family 1 (high affinity aspartate/glutamate transporter), member 6 FLJ40365 19p13.13 hypothetical protein FLJ40365 CASP14 19p13.1 caspase 14, apoptosis-related cysteine protease LOC126370 19p13.13 similar to Olfactory receptor 1I1 (Olfactory receptor 19-20) (OR19-20) 7h3 19p13.13 hypothetical protein FLJ13511 ILVBL 19p13.1 ilvB (bacterial acetolactate synthase)-like NOTCH3 19p13.2-p13.1 Notch homolog 3 (Drosophila) ABHD9 19p13.13 abhydrolase domain containing 9 BRD4 19p13.1 bromodomain containing 4 AKAP8 19p13.1-q12 a kinase (PRKA) anchor protein 8 NAKAP95 19p13.12-p13.11 a kinase (PRKA) anchor protein 8 WIZ 19p13.1 widely-interspaced zinc finger motifs FLJ21438 19p13.12 hypothetical protein FLJ21438 PGRP-L 19p13.12 peptidoglycan recognition protein L precursor FLJ39501 19p13.12 hypothetical protein FLJ39501 LOC390896 19 similar to Cytochrome P450 4F6 (CYPIVF6) LOC388513 19 similar to 60S ribosomal protein L23a CYP4F8 19p13.1 cytochrome P450, family 4, subfamily F, polypeptide 8
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    20 - 5198 152 1362 - 2009 19103749
  • BRD4l
  • a C-terminal extension including a proline-rich region and a glutamine-rich region
  • long isoform
  • 12 splicing 4635 80.5 722 - 2009 19103749
  • BRD4s, variant lacking exons 12-19
  • short isoform
  • 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 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