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Review
. 2016 Nov 7;17(11):1849.
doi: 10.3390/ijms17111849.

The Bromodomain and Extra-Terminal Domain (BET) Family: Functional Anatomy of BET Paralogous Proteins

Yasushi Taniguchi  1
Affiliations
Review

The Bromodomain and Extra-Terminal Domain (BET) Family: Functional Anatomy of BET Paralogous Proteins

Yasushi Taniguchi. Int J Mol Sci. .

Abstract

The Bromodomain and Extra-Terminal Domain (BET) family of proteins is characterized by the presence of two tandem bromodomains and an extra-terminal domain. The mammalian BET family of proteins comprises BRD2, BRD3, BRD4, and BRDT, which are encoded by paralogous genes that may have been generated by repeated duplication of an ancestral gene during evolution. Bromodomains that can specifically bind acetylated lysine residues in histones serve as chromatin-_targeting modules that decipher the histone acetylation code. BET proteins play a crucial role in regulating gene transcription through epigenetic interactions between bromodomains and acetylated histones during cellular proliferation and differentiation processes. On the other hand, BET proteins have been reported to mediate latent viral infection in host cells and be involved in oncogenesis. Human BRD4 is involved in multiple processes of the DNA virus life cycle, including viral replication, genome maintenance, and gene transcription through interaction with viral proteins. Aberrant BRD4 expression contributes to carcinogenesis by mediating hyperacetylation of the chromatin containing the cell proliferation-promoting genes. BET bromodomain blockade using small-molecule inhibitors gives rise to selective repression of the transcriptional network driven by c-MYC These inhibitors are expected to be potential therapeutic drugs for a wide range of cancers. This review presents an overview of the basic roles of BET proteins and highlights the pathological functions of BET and the recent developments in cancer therapy _targeting BET proteins in animal models.

Keywords: BET inhibitor; Bromodomain and Extra-Terminal Domain (BET); bromodomain; gene transcription; histone acetylation.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
Structure of the mouse Bromodomain and Extra-Terminal Domain (BET) (Brd2, Brd3, Brd4, and Brdt), amphioxus BET, Drosophila fsh and yeast Bdf1 genes, and the proteins encoded by these genes. Rectangles filled in yellowish green represent individual exons on genomic DNA. Long and short forms of an exon, which share the same nucleotide sequence, are classified by a decimal. Successive rectangles filled in yellow represent the primary structure of the proteins. The numbers in rectangles show areas encoded by the corresponding exons. Red, blue, and green areas indicate bromodomains (BDI, BDII, and truncated ∆BDII), extra-terminal domains (ET), and C-terminal domains (CTD), respectively. The total number of amino acids comprising the protein is represented on the right of each primary protein structure. In amphioxus, partial structures are depicted on the basis of the information in the Data Bank. The nucleotide sequences of BET genes and amino acid sequences of BET proteins are based on the database information provided in the following accession numbers: Brd2: D89801 and AB212273; Brd3-S: AB212272; Brd3-L: AB206708; Brd4-S: AF461396; Brd4-L: AF273217; Brdt-S: AB208640; Brdt-L: AF358660; amphioxus BET: AF391288; FSH-S: M23222; FSH-L: M23221; and Bdf1, Z18944.
Figure 1
Figure 1
Structure of the mouse Bromodomain and Extra-Terminal Domain (BET) (Brd2, Brd3, Brd4, and Brdt), amphioxus BET, Drosophila fsh and yeast Bdf1 genes, and the proteins encoded by these genes. Rectangles filled in yellowish green represent individual exons on genomic DNA. Long and short forms of an exon, which share the same nucleotide sequence, are classified by a decimal. Successive rectangles filled in yellow represent the primary structure of the proteins. The numbers in rectangles show areas encoded by the corresponding exons. Red, blue, and green areas indicate bromodomains (BDI, BDII, and truncated ∆BDII), extra-terminal domains (ET), and C-terminal domains (CTD), respectively. The total number of amino acids comprising the protein is represented on the right of each primary protein structure. In amphioxus, partial structures are depicted on the basis of the information in the Data Bank. The nucleotide sequences of BET genes and amino acid sequences of BET proteins are based on the database information provided in the following accession numbers: Brd2: D89801 and AB212273; Brd3-S: AB212272; Brd3-L: AB206708; Brd4-S: AF461396; Brd4-L: AF273217; Brdt-S: AB208640; Brdt-L: AF358660; amphioxus BET: AF391288; FSH-S: M23222; FSH-L: M23221; and Bdf1, Z18944.
Figure 2
Figure 2
The tertiary structure of the human BRD4-BDI complex with the inhibitor JQ1. A long loop (loop ZA) connects helices αZ and αA, and another loop (loop BC) connects helices αB and αC. A pocket-shaped region formed by these two loops is a binding site for JQ1 or an acetylated lysine residue in histones. The small molecule seen in the pocket is the inhibitor JQ1. The structure of BRD4-BDI is based on the NCBI database information provided in the accession number 3MXF_A.
Figure 3
Figure 3
Transcriptional control by BET proteins. (A) Brd2 and Brd3 promote gene transcription. Interactions between their bromodomains (BD) and the acetylated lysine (Ac) in histones facilitate the passage of RNA Pol II to elongate nascent transcripts through hyperacetylated nucleosomes. The arrow indicates the direction of transcription; (B) Brd4 regulates gene transcription in the process of initiation and elongation. In the promoter-proximal region, RNA Pol II pauses due to inactivation of positive transcription elongation factor b (P-TEFb), forming a complex with the 7SK small nuclear RNA (snRNA) and the HEXIM1 protein. Enhanced recruitment of P-TEFb by Brd4 causes Ser2 phosphorylation in Pol II, leading to Pol II release from the pause in transcription elongation. The pause release is also supported by the interaction of P-TEFb with Brd4 and JMJD6 associated with distal enhancers. Brd4 interacts with acetylated lysine through its bromodomains (the red circle in Brd4), and P-TEFb interacts with the Brd4 CTD (the green area in Brd4). Further, Brd4 promotes nascent RNA synthesis along the gene on hyperacetylated nucleosomes via its bromodomains.
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