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FLASH GENE

Symbol

BRD4

contributors: mct/pgu - updated : 29-12-2017

HGNC name	bromodomain containing 4
HGNC id	13575

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_058243 20 - 5198 NP_490597 152 1362 - 2009 19103749 BRD4l a C-terminal extension including a proline-rich region and a glutamine-rich region long isoform NM_014299 12 splicing 4635 NP_055114 80.5 722 - 2009 19103749 BRD4s, variant lacking exons 12-19 short isoform

EXPRESSION

Type	ubiquitous

expressed in

(based on citations)

organ(s)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive intestine large intestine colon   moderately   liver       moderately Lymphoid/Immune lymph node       predominantly   thymus       highly Reproductive female system ovary     moderately   female system placenta     moderately Respiratory lung       moderately   respiratory tract larynx     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
	BRD2, BRD3, BRD4, and BRDT are transcriptional regulators required for efficient expression of several growth promoting and antiapoptotic genes as well as for cell-cycle progression
	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 and the GBAF complex cooperate in regulating the naive pluripotency program (pMID: 30510198)
	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
	BRD9 interacts with BRD4 in a bromodomain-dependent fashion, which leads to the recruitment of GBAF complexes to chromatin, explaining the functional similarity between these epigenetic regulators

cell & other

REGULATION

inhibited by

JQ1, a selective and potent inhibitor of BET family bromodomains

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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
	System Type Disorder Pubmed cancer hemopathy   inhibition of BRD4 is a promising therapeutic strategy in AML (acute myeloid leukaemia) and, potentially, other cancers cancer hemopathy   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 cancer digestive liver is a potential novel target for the development of therapeutic approaches against HCC cancer     inhibition of the BET-histone interaction results in transcriptional downregulation of a number of oncogenes, providing a novel pharmacologic strategy for the treatment of cancer

ANIMAL & CELL MODELS

Brd4-depleted mice display reversible epidermal hyperplasia, alopecia, and decreased cellular diversity and stem cell depletion in the small intestine