Bromodomains

Although some bromodomain-containing proteins have been studied in detail, allowing some association with specific diseases, the roles of many bromodomains are unknown. 

Within the BET family, BRD2 is genetically associated with juvenile myoclonic epilepsy. Although complete knockout in mice results in embryonic lethality (with neural tube defects as a major pathology), targeted reduction in expression by promoter disruption in adult mice causes an unusual obese phenotype without type 2 diabetes.  

PBl (polybromo-1 protein) is a subunit of the PBAF (polybromo, Brgl-associated factors) chromatin-remodelling complex required for kinetochore localisation during mitosis and the transcription of estrogen-responsive genes. 

Subfamily Bromodomain Cognate sequence Biological rolejdisease association 

BET (BRD2, BRD3, BRD4, BRD8, BRDT) BRD2 H4K5/8/12/16 Epilepsy 

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In addition protein domains have been identified which bind to modified histone tails. The so-called bromodomains bind to acetylated histone tail, but have little or no affinity to unmodified tails. Further known binding domains include chromodomains and SANT domains which possess preferential binding to methylated and unmodified tails. 

Jeanmougin F, Wurtz JM, Le Douarin B, Chambon P, Losson R (1997) The bromodomain revisited. Trends Biochem Sci 22 151—153... 

Winston F, Allis CD (1999) The bromodomain a chromatin-targeting module Nat Struct Biol 6 601-604... 

In contrast to simple charge neutralization effects, the effects on protein recog-nition/recruitment are collectively referred to as the histone code . This hypothesis predicts that specific patterns of histone tail acetylations and other modifications serve as epigenetic marks for distinct sets of regulatory proteins to differentially modulate chromatin structure and function (Strahl and Allis, 2000 Turner, 2000 Jenuwein and Allis, 2001). Indeed, several recent findings have demonstrated that histone acetylation creates a signal for the binding of a bromodomain which has... 

Hassan AH, Prochasson P, Neely KE, Galasinski SC, Chandy M, Carrozza MJ, Workman JL (2002) Function and selectivity of bromodomains in anchoring chromatin-modifying complexes to promoter nucleosomes. Cell 111 369-379... 

Kanno T, Kanno Y, Siegel RM, Jang MK, Lenardo MJ, Ozato K (2004) Selective recognition of acetylated histones by bromodomain proteins visualized in living cells. Mol Cell 13 33-43... 

Zeng L, Zhou MM (2002) Bromodomain an acetyl-lysine binding domain. EEBS letters 513 124-128 Zhang Y, Reinberg D (2001) Transcription regulation by histone methylation interplay between different covalent modifications of the core histone tails. Genes Dev 15 2343-2360... 

Dorr A, Kiermer V, Pedal A, Rackwitz HR, HenUein P, Schubert U, Zhou MM, Verdin E, Ott M (2002) Transcriptional synergy between Tat and PCAF is dependent on the binding of acetylated Tat to the PCAF bromodomain. EMBO J 21 2715-2723... 

Nicolas, R.H. and Goodwin, G.H. (1996) Molecular cloning of polybromo, a nuclear protein containing multiple domains including five bromodomains, a truncated HMG-box, and two repeats of a novel domain. Gene 175, 233-240. 

Marmorstein, R. and Berger, S.L. (2001) Structure and function of bromodomains in chromatinregulating complexes. Gene 272, 1-9. 

It has been known for some time that certain bromodomains, sequence elements found in many chromatin associated proteins and most HATs [79], bind preferentially to acetylated peptides in in vitro binding assays, leading to speculation that acetylated histone tails could form targets for the binding of bromodomain-containing proteins in vivo [80,81]. Recent experiments provide direct evidence for this. 

Jacobson, R.H., Ladurner, A.G., King, D.S., and Tjian, R. (2000) Structure and function of a human TAFII250 double bromodomain module. Science 288, 1422-1425. 

The co-repressor KAP-1 functionally links the DNA-binding Kruppel-associated box zinc finger proteins to the NURD complex by recruiting the Mi-2a subunit. [251]. This interaction requires a tandem PHD/bromodomain motif in which the individual domains appear to act together as a functional unit. The nature of any possible acetylated lysine targets of the bromodomain remains unclear but it is not excluded that this domain could bind to an acetylated lysine in Mi-2a rather than to an acetylated histone tail. 

Cairns, B.R., Schlichter, A., Erdjument-Bromage, H., Tempst, P., Kornberg, R.D., and Winston, F. (1999) Two functionally distinct forms of the RSC nucleosome-remodeling complex, containing essential AT hook, BAH, and bromodomains. Mol. Cell 4, 715-723. 

Schultz, D.C., Friedman, J.R., and Rauscher, F.J., 3rd. (2001) Targeting histone deacetylase complexes via KRAB-zinc finger proteins the PHD and bromodomains of KAP-1 form a cooperative unit that recruits a novel isoform of the Mi-2a subunit of NuRD, Genes Dev. 15, 428-443. 

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