BRD4 (bromodomain containing 4)

2007-02-01   Anna Collin 

Department of Clinical Genetics, University Hospital, SE-221 85 Lund, Sweden

Identity

HGNC
LOCATION
19p13.12
LOCUSID
ALIAS
CAP,HUNK1,HUNKI,MCAP
FUSION GENES

DNA/RNA

Description

The gene consists of 20 exons that span approximately 43 kb of genomic DNA in the centromere-to-telomere orientation. The translation initiation codon and stop codon are located to exon 2 and exon 20, respectively.

Transcription

Two isoforms of BRD4 have been reported. The "BRD4 long isoform" corresponds to the ordinary full length transcript while the "BRD4 short isoform" corresponds to an alternative splicing variant lacking exons 12-20. The "BRD4 long variant" encodes a 6.0 kb transcript and the "BRD4 short variant" encodes a 4.4 kb transcript.

Proteins

Description

BRD4 belongs to the BET subgroup of the bromodomain superfamily and contains 2 bromodomains and a conserved ET-domain.
The open reading frame encodes a 1362 amino acid protein with a molecular weight of 200 kDa.

Expression

Northen blot analysis has shown an ubiquitous normal expression of both BRD4 isoforms.

Localisation

Nuclear.

Function

A striking feature of BRD4 is its association with euchromatic regions of mitotic chromosomes. By this association, the protein exerts its function as regulator of cell cycle progression from G2 to M but also in the G1 to S transition. It has also been suggested that the association of BRD4 to chromatin is important for the transmission of a transcriptional memory during cell division.

Implicated in

Entity name
Carcinoma with t(15;19)(q14;p13) translocation.
Prognosis
Carcinoma with t(15;19) translocation is invariably fatal with a rapid clinical course when located to the midline thoracic, head and neck structures. One tumor, displaying the cytogenetic and molecular cytogenetic features of carcinoma with t(15;19) translocation, but located to the iliac bone, has been reported as successfully cured.
Cytogenetics
t(15;19)(q14;p13) [reported breakpoints: t(15;19)(q11-15;p13)].
Hybrid gene
The t(15;19)(q14;p13) results in a BRD4-NUT chimeric gene where exon 10 of BRD4 is fused to exon 2 of NUT.
Fusion protein
The BRD4-NUT fusion protein is composed of the N-terminal of BRD4 (amino acids 1-720 out of 1372) and almost the entire protein sequence of NUT (amino acids 6-1127). The N-terminal of BRD4 includes bromodomains 1 and 2 and other, less well characterized functional domains.
Oncogenesis
It has been suggested that the oncogenic effect of the NUT-BRD4 fusion is caused not only by the abnormal regulation of NUT by BRD4 promoter elements but also by the consequent ectopic expression of NUT in non-germinal tissues.

Breakpoints

Note

The vast majority of reported 19p breakpoints were assigned to band 19p13, the exception being the cytogenetic interpretation of a 19q13 breakpoint reported once. The reported breakpoints on chromosome 15 have varied (15q11-q15).

Bibliography

Pubmed IDLast YearTitleAuthors
128401452003The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis.Dey A et al
109381292000A bromodomain protein, MCAP, associates with mitotic chromosomes and affects G(2)-to-M transition.Dey A et al
165424422006Midline carcinoma with t(15;19) and BRD4-NUT fusion oncogene in a 30-year-old female with response to docetaxel and radiotherapy.Engleson J et al
114874682001You bet-cha: a novel family of transcriptional regulators.Florence B et al
154830232004Midline carcinoma of children and young adults with NUT rearrangement.French CA et al
125437792003BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma.French CA et al
17856731991Intrathoracic carcinoma in an 11-year-old girl showing a translocation t(15;19).Kees UR et al
121920492002A Mammalian bromodomain protein, brd4, interacts with replication factor C and inhibits progression to S phase.Maruyama T et al
164353792007Successful treatment of a child with t(15;19)-positive tumor.Mertens F et al
151094952004Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes.You J et al

Other Information

Locus ID:

NCBI: 23476
MIM: 608749
HGNC: 13575
Ensembl: ENSG00000141867

Variants:

dbSNP: 23476
ClinVar: 23476
TCGA: ENSG00000141867
COSMIC: BRD4

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000141867ENST00000263377O60885
ENSG00000141867ENST00000360016O60885
ENSG00000141867ENST00000360016A0A024R7H8
ENSG00000141867ENST00000371835O60885
ENSG00000141867ENST00000594841M0QZD9
ENSG00000141867ENST00000597315M0QYW0
ENSG00000141867ENST00000601941M0R0H4
ENSG00000141867ENST00000630599M0QYW0

Expression (GTEx)

0
5
10
15
20
25
30
35
40

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
191037492009Brd4 coactivates transcriptional activation of NF-kappaB via specific binding to acetylated RelA.208
215554542011The Brd4 extraterminal domain confers transcription activation independent of pTEFb by recruiting multiple proteins, including NSD3.190
151094952004Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes.186
176902452007Conserved P-TEFb-interacting domain of BRD4 inhibits HIV transcription.163
245252352014Disrupting the interaction of BRD4 with diacetylated Twist suppresses tumorigenesis in basal-like breast cancer.161
180398612008Brd4 recruits P-TEFb to chromosomes at late mitosis to promote G1 gene expression and cell cycle progression.143
243602792013Brd4 and JMJD6-associated anti-pause enhancers in regulation of transcriptional pause release.139
245840722014An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia.121
233175042013Phospho switch triggers Brd4 chromatin binding and activator recruitment for gene-specific targeting.119
179345172008BRD-NUT oncoproteins: a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells.118

Citation

Anna Collin

BRD4 (bromodomain containing 4)

Atlas Genet Cytogenet Oncol Haematol. 2007-02-01

Online version: http://atlasgeneticsoncology.org/gene/837/brd4-(bromodomain-containing-4)