Skip to main content
SpringerLink
Log in

The Bromodomain as the Acetyl-Lysine Binding Domain in Gene Transcription

  • Chapter
  • First Online:
Histone Recognition

  • 954 Accesses

Abstract

The bromodomain (BrD), a conserved structural module found in many chromatin- and transcription-associated proteins, is the primary reader of acetylated lysine residues on proteins. Since the discovery of this domain, the study of BrD-containing proteins has provided tremendous insights into many important mechanisms in chromatin biology and also shown that inhibitors of BrDs can be useful both as chemical tools in the laboratory and as therapeutics in the clinic. BrDs often function in concert with other similar modular domains on chromatin-associated proteins, creating a very complex system of epigenetic regulation that is currently under investigation by numerous researchers. In this chapter, we take a closer look at the structure and functions of the BrD, as well as its interaction with other chromatin-associated modules and its overall role in disease biology.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  • Albrecht BK, Audia JE, Cote A, Gehling VS, Harmange J-C, Hewitt MC, LeBlanc Y, Naveschuk CG, Taylor AM, Vaswani RG (2014) Inventors; constellation pharmaceuticals, Inc., assignee. Bromodomain Inhibitors and Uses Thereof. USA2012

    Google Scholar 

  • Anand P, Brown JD, Lin CY, Qi J, Zhang R, Artero PC, Alati MA, Bullard J, Alazem K, Margulies KB, Cappola TP, Lemieux M, Plutzky J, Bradner JE, Haldar SM (2013) BET bromodomains mediate transcriptional pause release in heart failure. Cell 154:569–582

    PubMed Central  CAS  PubMed  Google Scholar 

  • Asangani IA, Dommeti VL, Wang X, Malik R, Cieslik M, Yang R, Escara-Wilke J, Wilder-Romans K, Dhanireddy S, Engelke C, Iyer MK, Jing X, Wu Y-M, Cao X, Qin ZS, Wang S, Feng FY, Chinnaiyan AM (2014) Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature 510(7504):278–282

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bamborough P, Diallo H, Goodacre JD, Gordon L, Lewis A, Seal JT, Wilson DM, Woodrow MD, Chung C-W (2012) Fragment-based discovery of bromodomain inhibitors part 2: optimization of phenylisoxazole sulfonamides. J Med Chem 55:587–596

    Google Scholar 

  • Bannister AJ, Kouzarides T (2005) Reversing histone methylation. Nature 436(7054):1103–1106

    CAS  PubMed  Google Scholar 

  • Basu MK, Carmel L, Rogozin IB, Koonin EV (2008) Evolution of protein domain promiscuity in eukaryotes. Genome Res 18(3):449–461

    PubMed Central  CAS  PubMed  Google Scholar 

  • Basu MK, Poliakov E, Rogozin IB (2009) Domain mobility in proteins: functional and evolutionary implications. Brief Bioinform 10(3):205–216

    PubMed Central  CAS  PubMed  Google Scholar 

  • Becker PB, Workman JL (2013) Nucleosome remodeling and epigenetics. Cold Spring Harb Perspect Biol 5(9):1–19

    Google Scholar 

  • Belkina AC, Denis GV (2012) BET domain co-regulators in obesity, inflammation and cancer. Nat Rev Cancer 12:465–477

    PubMed Central  CAS  PubMed  Google Scholar 

  • Boehm D, Calvanese V, Dar RD, Xing S, Schroeder S, Martins L, Aull K, Li P-C, Planelles V, Bradner JE, Zhou M-M, Siliciano RF, Weinberger L, Verdin E, Ott M (2013) BET bromodomain-targeting compounds reactivate HIV from latency via a Tat-independent mechanism. Cell Cycle 12(3):452–462

    PubMed Central  CAS  PubMed  Google Scholar 

  • Borah JC, Mujtaba S, Karakikes I, Zeng L, Muller M, Patel J, Moshkina N, Morohashi K, Zhang W, Gerona-Navarro G, Hajjar RJ, Zhou M-M (2011) A small molecule binding to the coactivator CREB-binding protein blocks apoptosis in cardiomyocytes. Chem Biol 18:531–541

    PubMed Central  CAS  PubMed  Google Scholar 

  • Capili AD, Schultz DC III (2001) FJR, borden KLB. Solution structure of the PHD domain from the KAP-1 corepressor: structural determinants for PHD, RING and LIM zinc-binding domains. EMBO J 20(1):165–177

    PubMed Central  CAS  PubMed  Google Scholar 

  • Carlsten JOP, Zhu X, Gustafsson CM (2013) The multitalented mediator complex. Trends Biochem Sci 38(11):531–537

    CAS  PubMed  Google Scholar 

  • Cheng Z, Gong Y, Ma Y, Lu K, Lu X, Pierce LA, Thompson RC, Muller S, Knapp S, Wang J (2013) Inhibition of BET bromodomain targets genetically diverse glioblastoma. Clin Cancer Res 19(7):1–12

    Google Scholar 

  • Chi P, Allis CD, Wang GG (2010) Covalent histone modifications—miswritten, misinterpreted and MIS-erased in human cancers. Nature Reviews 10(7):457–69; PubMed Central PMCID: PMC3262678

    Google Scholar 

  • Chiang C-M (2009) Brd4 engagement from chromatin targeting to transcriptional regulation: selective contact with acetylated histone H3 and H4. F1000 Biol Rep 1

    Google Scholar 

  • Chou K-C, Maggiora GM, Nemethy G, Scheraga HA (1988) Energetics of the structure of the four-alpha-helix bundle in proteins. Proc Natl Acad Sci USA 85:4295–4299

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chung C-W, Dean AW, Woolven JM, Bamborough P (2012) Fragment-based discovery of bromodomain inhibitors part 1: inhibitor binding modes and implications for lead discovery. J Med Chem 55:576–586

    Google Scholar 

  • Clapier CR, Cairns BR (2009) The biology of chromatin remodeling complexes. Annu Rev Biochem 78:273–304

    CAS  PubMed  Google Scholar 

  • Conaway RC, Conaway JW (2011) Function and regulation of the mediator complex. Curr Opin Genet Dev 21(2):225–230

    PubMed Central  CAS  PubMed  Google Scholar 

  • Crawford NPS, Alsarraj J, Lukes L, Walker RC, Officewala JS, Yang HH, Lee MP, Ozato K, Hunter KW (2008) Bromodomain 4 activation predicts breast cancer survival. Proc Natl Acad Sci USA 105(17):6380–6385

    PubMed Central  CAS  PubMed  Google Scholar 

  • Dawson MA, Prinjha RK, Dittmann A, Giotopoulos G, Bantscheff M, Chan W-I, Robson SC, Chung C-w, Hopf C, Savitski MM, Huthmacher C, Gudgin E, Lugo D, Beinke S, Chapman TD, Roberts EJ, Soden PE, Auger KR, Mirguet O, Doehner K, Delwel R, Burnett AK, Jeffrey P, Drewes G, Lee K, Huntly BJP, Kouzarides T (2011) Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478:529–533; PubMed Central PMCID: PMC3679520

    Google Scholar 

  • Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, Kastritis E, Gilpatrick T, Paranal RM, Qi J, Chesi M, Schinzel AC, McKeown MR, Heffernan TP, Vakoc CR, Bergsagel PL, Ghobrial IM, Richardson PG, Young RA, Hahn WC, Anderson KC, Kung AL, Bradner JE, Mitsiades CS (2011) BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146:904–917; PubMed Central PMCID: PMC3187920

    Google Scholar 

  • Delvecchio M, Gaucher J, Aguilar-Gurrieri C, Ortega E, Panne D (2013) Structure of the p300 catalytic core and implications for chromatin targeting and HAT regulation. Nat Struct Mol Biol 20(9):1040–1046

    CAS  PubMed  Google Scholar 

  • Devaiah BN, Lewis BA, Cherman N, Hewitt MC, Albrecht BK, Robey PG, Ozato K, Robert J. Sims I, Singer DS (2012) BRD4 is an atypical kinase that phosphorylates serine2 of the RNA polymerase II carboxy-terminal domain. Proc Natl Acad Sci USA 109(18):6927–6932

    Google Scholar 

  • Dey A, Ellenberg J, Farina A, Coleman AE, Maruyama T, Sciortino S, Lippincott-Schwartz J, Ozato K (2000) A bromodomain protein, MCAP, associates with mitotic chromosomes and affects G2-to-M transition. Mol Cell Biol 20(17):6537–6549

    PubMed Central  CAS  PubMed  Google Scholar 

  • Dey A, Chitsaz F, Abbasi A, Misteli T, Ozato K (2003) The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis. Proc Natl Acad Sci USA 100(15):8758–8763

    PubMed Central  CAS  PubMed  Google Scholar 

  • Dey A, Nishiyama A, Karpova T, McNally J, Ozato K (2009) Brd4 marks select genes on mitotic chromatin and directs postmitotic transcription. Mol Biol Cell 20:4899–4909

    PubMed Central  CAS  PubMed  Google Scholar 

  • Dhalluin C, Carlson JE, Zeng L, He C, Aggarwal AK, Zhou M-M (1999) Structure and ligand of a histone acetyltransferase bromodomain. Nature 399:491–496

    CAS  PubMed  Google Scholar 

  • Filippakopoulos P, Knapp S (2012) The bromodomain interaction module. FEBS Lett 586(17):2692–2704

    CAS  PubMed  Google Scholar 

  • Filippakopoulos P, Knapp S (2014) Targeting bromodomains: epigenetic readers of lysine acetylation. Nat Rev Drug Disc Epub 22 April 2014. doi: 10.1038/nrd4286

  • Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, Morse EM, Keates T, Hickman TT, Felletar I, Philpott M, Munro S, McKeown MR, Wang Y, Christie AL, West N, Cameron MJ, Schwartz B, Heightman TD, Thangue NL, French CA, Wiest O, Kung AL, Knapp S, Bradner JE (2010) Selective inhibition of BET bromodomains. Nature 468:1067–1073; PubMed Central PMCID: PMC3010259

    Google Scholar 

  • Filippakopoulos P, Picaud S, Mangos M, Keates T, Lambert J-P, Barsyte-Lovejoy D, Felletar I, Volkmer R, Muller S, Pawson T, Gingras A-C, Arrowsmith CH, Knapp S (2012) Histone recognition and large-scale structural analysis of the human bromodomain family. Cell 149:214–231

    PubMed Central  CAS  PubMed  Google Scholar 

  • Floyd SR, Pacold ME, Huang Q, Clarke SM, Lam FC, Cannell IG, Bryson BD, Rameseder J, Lee MJ, Blake EJ, Fydrych A, Ho R, Greenberger BA, Chen GC, Maffa A, Rosario AMD, Root DE, Carpenter AE, Hahn WC, Sabatini DM, Chen CC, White FM, Bradner JE, Yaffe MB (2013) The bromodomain protein Brd4 insulates chromatin from DNA damage signalling. Nature 498(7453):246–250

    PubMed Central  CAS  PubMed  Google Scholar 

  • French CA, Miyoshi I, Aster JC, Kubonishi I, Kroll TG, Cin PD, Vargas SO, Perez-Atayde AR, Fletcher JA (2001) BRD4 Bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19). Am J Pathol 159(6):1987–1992

    PubMed Central  CAS  PubMed  Google Scholar 

  • French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA (2003) BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res 63:304–307

    CAS  PubMed  Google Scholar 

  • French C, Ramirez C, Kolmakova J, Hickman T, Cameron M, Thyne M, Kutok J, Toretsky J, Tadavarthy A, Kees U, Fletcher J, Aster J (2008) BRD-NUT oncoproteins: a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells. Oncogene 27:2237–2242

    CAS  PubMed  Google Scholar 

  • Fuda NJ, Ardehali MB, Lis JT (2009) Defining mechanisms that regulate RNA polymerase II transcription in vivo. Nature 461:186–192

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gacias M, Gerona-Navarro G, Plotnikov AN, Zhang G, Zeng L, Kaur J, Moy G, Rusinova E, Rodriguez Y, Matikainen B, Vincek A, Joshua J, Casaccia P, Zhou M-M (2014) Selective chemical modulation of gene transcription favors oligodendrocyte lineage progression. Chem Biol 21:841–854

    CAS  PubMed  Google Scholar 

  • Gagnon D, Joubert S, Senechal H, Fradet-Turcotte A, Torre S, Archambault J (2009) Proteasomal degradation of the papillomavirus E2 protein is inhibited by overexpression of bromodomain-containing protein 4. J Virol 83(9):4127–4139

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gamsjaeger R, Webb SR, Lamonica JM, Billin A, Blobel GA, Mackay JP (2011) Structural basis and specificity of acetylated transcription factor GATA1 recognition by BET family bromodomain protein Brd3. Mol Cell Biol 31(13):2632–2640

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gerona-Navarro G, Rodriguez Y, Mujtaba S, Frasca A, Patel J, Zeng L, Plotnikov AN, Osman R, Zhou M-M (2011) Rational design of cyclic peptide modulators of the transcriptional coactivator CBP: a new class of p53 inhibitors. J Am Chem Soc 133:2040–2043

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gil J, Bernard D, Martinez D, Beach D (2004) Polycomb CBX7 has a unifying role in cellular lifespan. Nat Cell Biol 6(1):67–72

    CAS  PubMed  Google Scholar 

  • Gilmore TD (1999) The Rel/NF-KB signal transduction pathway: introduction. Oncogene 18:6842–6844

    CAS  PubMed  Google Scholar 

  • Gregory GD, Vakoc CR, Rozovskaia T, Zheng X, Patel S, Nakamura T, Canaani E, Blobel GA (2007) Mammalian ASH1L is a histone methyltransferase that occupies the transcribed region of active genes. Mol Cell Biol 27(24):8466–8479

    PubMed Central  CAS  PubMed  Google Scholar 

  • Harikrishnan KN, Chow MZ, Baker EK, Pal S, Bassal S, Brasacchio D, Wang L, Craig JM, Jones PL, Sif S, El-Osta A (2005) Brahman links the SWI/SNF chromatin-remodeling complex with MeCP2-dependent transcriptional silencing. Nat Genet 37(3):254–264

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Hassan AH, Awad S, Prochasson P (2006) The Swi2/Snf2 Bromodomain Is required for the displacement of SAGA and the octamer transfer of SAGA-acetylated nucleosomes. J Biol Chem 281(26):18126–18134

    CAS  PubMed  Google Scholar 

  • Hayden MS, Ghosh S (2004) Signaling to NF-KB. Genes Dev 18:2195–2224

    CAS  PubMed  Google Scholar 

  • Hewings DS, Wang M, Philpott M, Fedorov O, Uttarkar S, Filippakopoulos P, Picaud S, Vuppusetty C, Marsden B, Knapp S, Conway SJ, Heightman TD (2011) 3,5-dimethylisoxazoles act as acetyl-lysine-mimetic bromodomain ligands. J Med Chem 54:6761–6770

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-Andre V, Sigova AA, Hoke HA, Young RA (2013) Super-enhancers in the control of cell identity and disease. Cell 155:934–947

    CAS  PubMed  Google Scholar 

  • Hoffmann A, Natoli G, Ghosh G (2006) Transcriptional regulation via the NF-KB signaling module. Oncogene 25:6706–6716

    CAS  PubMed  Google Scholar 

  • Horn P, Peterson C (2001) The bromodomain: a regulator of ATP-dependent chromatin remodeling? Front Biosci 6:D1019–D1023

    CAS  PubMed  Google Scholar 

  • Huang B, Yang X-D, Zhou M-M, Ozato K, Chen L-F (2009) Brd4 coactivates transcriptional activation of NF-KB via specific binding to acetylated RelA. Mol Cell Biol 29(5):1375–1387

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ivanov AV, Peng H, Yurchenko V, Yap KL, Negorev DG, Schultz DC, Psulkowski E, Fredericks WJ, White DE, Maul GG, Sadofsky MJ, Zhou M-M III (2007) FJR. PHD Domain-mediated E3 ligase activity directs intramolecular sumoylation of an adjacent bromodomain required for gene silencing. Mol Cell 28:823–837

    PubMed Central  CAS  PubMed  Google Scholar 

  • Jacobson RH, Ladurner AG, King DS, Tijan R (2000) Structure and function of a human TAF(II)250 double bromodomain module. Science 288:1422–1425

    CAS  PubMed  Google Scholar 

  • Jang MK, Mochizuki K, Zhou M, Jeong H-S, Brady JN, Ozato K (2005) The bromodomain protein Brd4 Is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol Cell 19:523–534

    CAS  PubMed  Google Scholar 

  • Jeanmougin F, Wurtz J-M, Douarin BL, Chambon P, Losson R (1997) The bromodomain revisited. Trends Biochem Sci 22(5):151–153

    CAS  PubMed  Google Scholar 

  • Josling GA, Selvarajah SA, Petter M, Duffy MF (2012) The role of bromodomain proteins in regulating gene expression. Genes 3:320–343

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kagey MH, Newman JJ, Bilodeau S, Zhan Y, Orlando DA, Berkum NL, Ebmeier CC, Goossens J, Rahl PB, Levine SS, Taatjes DJ, Dekker J, Young RA (2010) Mediator and cohesion connect gene expression and chromatin architecture. Nature 467:430–435

    Google Scholar 

  • Kouzarides T (2007) Chromatin modifications and their function. Cell 128(4):693–705

    CAS  PubMed  Google Scholar 

  • Li H, Ilin S, Wang W, Duncan EM, Wysocka J, Allis CD, Patel DJ (2006) Molecular basis for site-specific read-out of histone H3K4me3 by the BPTF PHD finger of NURF. Nature 442(7098):91–95

    CAS  PubMed  Google Scholar 

  • Li Y, Wen H, Xi Y, Tanaka K, Wang H, Peng D, Ren Y, Jin Q, Dent SYR, Li W, Li H, Shi X (2014) AF9 YEATS domain links histone acetylation to DOT1L-Mediated H3K79 methylation. Cell 159:558–571

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lin Y-J, Umehara T, Inoue M, Saito K, Kigawa T, Jang M-K, Ozato K, Yokoyama S, Padmanabhan B, Guntert P (2008) Solution structure of the extraterminal domain of the bromodomain-containing protein BRD4. Protein Sci 17:2174–2179

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lucas X, Wohlwend D, Hugle M, Schmidtkunz K, Gerhardt S, Schule R, Jung M, Einsle O, Gunther S (2013) 4-acyl pyrroles: mimicking acetylated lysines in histone code reading. Angew Chem Int Ed 52:14055–14059

    CAS  Google Scholar 

  • Mele DA, Salmeron A, Ghosh S, Huang H-R, Bryant BM, Lora JM (2013) BET bromodomain inhibition suppresses TH17-mediated pathology. J Exp Med 210(11):2181–2190

    PubMed Central  CAS  PubMed  Google Scholar 

  • Mertz JA, Conery AR, Bryant BM, Sandy P, Balasubramanian S, Mele DA, Bergeron L, III RJS (2011) Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci USA 108(40):16669–16674; PubMed Central PMCID: PMC3189078

    Google Scholar 

  • Meslamani J, Smith SG, Sanchez R, Zhou M-M (2014) ChEpiMod: a knowledgebase for chemical modulators of epigenome reader domains. Bioinformatics 30(10):1481–1483

    Google Scholar 

  • Mills AA (2010) Throwing the cancer switch: reciprocal roles of polycomb and trithorax proteins. Nat Rev Cancer 10:669–682

    PubMed Central  CAS  PubMed  Google Scholar 

  • Milne TA, Briggs SD, Brock HW, Martin ME, Gibbs D, Allis CD, Hess JL (2002) MLL targets set domain methyltransferase activity to hox gene promoters. Mol Cell 10(5):1107–1117

    CAS  PubMed  Google Scholar 

  • Mirguet O, Lamotte Y, Donche Fdr, Toum Jrm, Gellibert Fo, Bouillot A, Gosmini R, Nguyen V-L, Delannée D, Seal J, Blandel F, Boullay A-Bnd, Boursier E, Martin S, Brusq J-M, Krysa G, Riou A, Tellier Rm, Costaz As, Huet P, Dudit Y, Trottet L, Kirilovsky J, Nicodeme E (2012) From ApoA1 upregulation to BET family bromodomain inhibition: discovery of I-BET151. Bioorg Med Chem Lett 22:2963–2967

    Google Scholar 

  • Mochizuki K, Nishiyama A, Jang MK, Dey A, Ghosh A, Tamura T, Natsume H, Yao H, Ozato K (2008) The bromodomain protein Brd4 stimulates G1 gene transcription and promotes progression to S phase. J Biol Chem 283(14):9040–9048

    PubMed Central  CAS  PubMed  Google Scholar 

  • Moriniere J, Rousseaux S, Steuerwald U, Soler-Lopez M, Curtet S, Vitte A-L, Govin J, Gaucher J, Sadoul K, Hart DJ, Krijgsveld J, Khochbin S, Muller CW, Petosa C (2009) Cooperative binding of two acetylation marks on a histone tail by a single bromodomain. Nature 461(7264):664–668

    CAS  PubMed  Google Scholar 

  • Mujtaba S, He Y, Zeng L, Farooq A, Carlson JE, Ott M, Verdin E, Zhou M-M (2002) Structural basis of lysine-acetylated HIV-1 tat recognition by PCAF bromodomain. Mol Cell 9(3):575–586

    CAS  PubMed  Google Scholar 

  • Mujtaba S, He Y, Zeng L, Yan S, Plotnikova O, Sachchidanand, Sanchez R, Zeleznik-Le NJ, Ronai Ze, Zhou M-M (2004) Structural mechanism of the bromodomain of the coactivator CBP in p53 transcriptional activation. Mole Cell 13:251–263

    Google Scholar 

  • Nicodeme E, Jeffrey KL, Schaefer U, Beinke S, Dewell S, Chung C-w, Chandwani R, Marazzi I, Wilson P, Coste H, White J, Kirilovsky J, Rice CM, Lora JM, Prinjha RK, Lee K, Tarahovsky A (2010) Suppression of inflammation by a synthetic histone mimic. Nature 468:1119–1123

    Google Scholar 

  • Ottinger M, Christalla T, Nathan K, Brinkmann MM, Viejo-Borbolla A, Schulz TF (2006) Kaposi’s sarcoma-associated herpesvirus LANA-1 interacts with the short variant of BRD4 and releases cells from a BRD4- and BRD2/RING3-Induced G1 cell cycle arrest. J Virol 80(21):10772–10786

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ottinger M, Pliquet D, Christalla T, Frank R, Stewart JP, Schulz TF (2009) The interaction of the gammaherpesvirus 68 orf73 protein with cellular BET proteins affects the activation of cell cycle promoters. J Virol 83(9):4423–4434

    PubMed Central  CAS  PubMed  Google Scholar 

  • Owen DJ, Ornaghi P, Yang J-C, Lowe N, Evans PR, Ballario P, Neuhaus D, Filetici P, Travers AA (2000) The structural basis for the recognition of acetylated histone H4 by the bromodomain of histone acetyltransferase Gcn5p. EMBO J 19(22):6141–6149

    PubMed Central  CAS  PubMed  Google Scholar 

  • Picaud S, Costa DD, Thanasopoulou A, Filippakopoulos P, Fish PV, Philpott M, Fedorov O, Brennan P, Bunnage ME, Owen DR, Bradner JE, Taniere P, O’Sullivan B, Muller S, Schwaller J, Stankovic T, Knapp S (2013a) PFI-1, a highly selective protein interaction inhibitor targeting BET bromodomains. Cancer Res 73(11):3336–3346

    PubMed Central  CAS  PubMed  Google Scholar 

  • Picaud S, Wells C, Felletar I, Brotherton D, Martin S, Savitsky P, Diez-Dacal B, Philpott M, Bountra C, Lingard H, Fedorov O, Muller S, Brennan PE, Knapp S, Filippakopoulos P (2013b) RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain. Proc Natl Acad Sci. doi:10.1073/pnas.1310658110

    PubMed Central  PubMed  Google Scholar 

  • Plotnikov AN, Yang S, Zhou TJ, Rusinova E, Frasca A, Zhou M-M (2014) Structural insights into acetylated-histone H4 recognition by the bromodomain-PHD finger module of human transcriptional coactivator CBP. Structure 22:353–360

    PubMed Central  CAS  PubMed  Google Scholar 

  • Presnell SR, Cohen FE (1989) Topological distribution of four-alpha-helix bundles. Proc Natl Acad Sci USA 86:6592–6596

    PubMed Central  CAS  PubMed  Google Scholar 

  • Price DH (2000) P-TEFb, a cyclin-dependent kinase controlling elongation by RNA polymerase II. Mol Cell Biol 20(8):2629–2634

    PubMed Central  CAS  PubMed  Google Scholar 

  • Prinjha RK, Witherington J, Lee K (2012) Place your BETs: the therapeutic potential of bromodomains. Trends Pharmacol Sci 33(3):146–153

    CAS  PubMed  Google Scholar 

  • Puissant A, Frumm SM, Alexe G, Bassil CF, Qi J, Chanthery YH, Nekritz EA, Zeid R, Gustafson WC, Greninger P, Garnett MJ, McDermott U, Benes CH, Kung AL, Weiss WA, Bradner JE, Stegmaier K (2013) Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov 3(3):308–323

    PubMed Central  CAS  PubMed  Google Scholar 

  • Rada-Iglesias A, Bajpai R, Swigut T, Brugmann SA, Flynn RA, Wysocka J (2011) A unique chromatin signature uncovers early developmental enhancers in humans. Nature 470(7333):279–283

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ragvin A, Valvatne H, Erdal S, Arskog V, Tufteland KR, Breen K, Oyan AM, Eberharter A, Gibson TJ, Becker PB, Aasland R (2004) Nucleosome binding by the bromodomain and PHD finger of the transcriptional cofactor p300. J Mol Biol 337:773–788

    CAS  PubMed  Google Scholar 

  • Rahman S, Sowa ME, Ottinger M, Smith JA, Shi Y, Harper JW, Howley PM (2011) The Brd4 extraterminal domain confers transcription activation independent of pTEFb by recruiting multiple proteins, including NSD3. Mol Cell Biol 31(13):2641–2652

    PubMed Central  CAS  PubMed  Google Scholar 

  • Richardson JS (1981) The anatomy and taxonomy of protein structure. Adv Prot Chem 34:167–339

    CAS  Google Scholar 

  • Rodriguez RM, Huidoboro C, Urdinguio RG, Mangas C, Soldevilla B, Dominguez G, Bonilla F, Fernandez AF, Fraga MF (2012) Aberrant epigenetic regulation of bromodomain Brd4 in human colon cancer. J Mol Med 90:587–595

    CAS  PubMed  Google Scholar 

  • Ruthenburg AJ, Li H, Patel DJ, Allis CD (2007) Multivalent engagement of chromatin modifications by linked binding modules. Nat Rev Mol Cell Biol 8:983–994

    CAS  PubMed  Google Scholar 

  • Ruthenburg AJ, Li H, Milne TA, Dewell S, McGinty RK, Yuen M, Ueberheide B, Dou Y, Muir TW, Patel DJ, Allis CD (2011) Recognition of a mononucleosomal histone modification pattern by BPTF via multivalent interactions. Cell 145:692–706

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sachchidanand, Resnick-Silverman L, Yan S, Mujtaba S, Liu W-j, Zeng L, Manfredi JJ, Zhou M-M (2006) Target structure-based discovery of small molecules that block human p53 and CREB binding protein association. Chem Biol 3:81–90

    Google Scholar 

  • Sanchez R, Zhou M-M (2009) The role of human bromodomains in chromatin biology and gene transcription. Curr Opin Drug Discov Devel 12(5):659–665

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sanchez R, Zhou M-M (2011) The PHD finger: a versatile epigenome reader. Trends Biochem Sci 36(7):364–72; PubMed Central PMCID: PMC3130114

    Google Scholar 

  • Sanchez R, Pieper U, Melo F, Eswar N, Marti-Renom MA, Madhusudhan MS, Mirkovic N, Sali A (2000) Protein structure modeling for structural genomics. Nat Struct Biol, Struct Genomics 7: 986–990

    Google Scholar 

  • Santos-Rosa H, Schneider R, Bannister AJ, Sherriff J, Bernstein BE, Emre NCT, Schreiber SL, Mellor J, Kouzarides T (2002) Active genes are tri-methylated at K4 of histone H3. Nature 419(6905):407–411

    CAS  PubMed  Google Scholar 

  • Schultz J, Copley RR, Doerks T, Ponting CP, Bork P (2000) SMART: a web-based tool for the study of genetically mobile domains. Nucleic Acids Res 28(1):231–234

    PubMed Central  CAS  PubMed  Google Scholar 

  • Seal J, Lamotte Y, Donche F, Bouillot A, Mirguet O, Gellibert F, Nicodeme E, Krysa G, Kirilovsky J, Beinke S, McCleary S, Rioja I, Bamborough P, Chung C-w, Gordon L, Lewis T, Walker AL, Cutler L, Lugo D, Wilson DM, Witherington J, Lee K, Prinjha RK (2012) Identification of a novel series of BET family bromodomain inhibitors: binding mode and profile of I-BET151 (GSK1210151A). Bioorg Med Chem 22:2968–2972

    Google Scholar 

  • Seet BT, Dikic I, Zhou M-M, Pawson T (2006) Reading protein modifications with interaction domains. Nat Rev Mol Cell Biol 7:473–483

    CAS  PubMed  Google Scholar 

  • Shi J, Wang Y, Zeng L, Wu Y, Deng J, Zhang Q, Lin Y, Li J, Kang T, Tao M, Rusinova E, Zhang G, Wang C, Zhu H, Yao J, Zeng Y-X, Evers BM, Zhou M-M, Zhou BP (2014) Disrupting the Interaction of BRD4 with diacetylated twist suppresses tumorigenesis in basal-like breast cancer. Cancer Cell 25:210–225

    PubMed Central  CAS  PubMed  Google Scholar 

  • Simon JA, Kingston RE (2009) Mechanisms of Polycomb gene silencing: knowns and unknowns. Nat Rev Mol Cell Biol 10(10):697–708

    CAS  PubMed  Google Scholar 

  • Simon JA, Kingston RE (2013) Occupying chromatin: polycomb mechanisms for getting to genomic targets, stopping transcriptional traffic, and staying put. Mol Cell 49(5):808–24; PubMed Central PMCID: PMC3628831

    Google Scholar 

  • Smith SG, Sanchez R, Zhou M-M (2014) Privileged diazepine compounds and their emergence as bromodomain inhibitors. Chem Biol Epub 15 April 2014. doi: 10.1016/j.chembiol.2014.03.004

  • Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403(6765):41–45

    CAS  PubMed  Google Scholar 

  • Tanaka Y, Katagiri Z-i, Kawahashi K, Kioussis D, Kitajima S (2007) Trithorax-group protein ASH1 methylates histone H3 lysine 36. Gene 397:161–168

    CAS  PubMed  Google Scholar 

  • Taverna SD, Li H, Ruthenburg AJ, Allis CD, Patel DJ (2007) How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat Struct Mol Biol 14(11):1025–1040

    CAS  PubMed  Google Scholar 

  • Thompson M (2009) Polybromo-1: the chromatin targeting subunit of the PBAF complex. Biochimie 91:309–319

    PubMed Central  CAS  PubMed  Google Scholar 

  • Tsai W-W, Wang Z, Yiu TT, Akdemir KC, Xia W, Winter S, Tsai C-Y, Shi X, Schwarzer D, Plunkett W, Aronow B, Gozani O, Fischle W, Hung M-C, Patel DJ, Barton MC (2010) TRIM24 links a non-canonical histone signature to breast cancer. Nature 468(7326):927–932

    PubMed Central  CAS  PubMed  Google Scholar 

  • Van Demark AP, Kasten MM, Ferris E, Heroux A, Hill CP, Cairns BR (2007) Autoregulation of the Rsc4 tandem bromodomain by Gcn5 acetylation. Mol Cell 27(5):817–828

    Google Scholar 

  • Vignali M, Hassan AH, Neely KE, Workman JL (2000) ATP-dependent chromatin-remodeling complexes. Mol Cell Biol 20(6):1899–1910

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wang GG, Allis CD, Chi P (2007) Chromatin remodeling and cancer, part I: covalent histone modifications. Trends Mol Med 13(9):363–372

    CAS  PubMed  Google Scholar 

  • Weber PC, Salemme FR (1980) Structural and functional diversity in 4-alpha-helical proteins. Nature 287:82–84

    CAS  PubMed  Google Scholar 

  • Wu S-Y, Chiang C-M (2007) The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation. J Biol Chem 282(18):13141–13145

    CAS  PubMed  Google Scholar 

  • Wu S-Y, Lee A-Y, Hou SY, Kemper JK, Erdjument-Bromage H, Tempst P, Chiang C-M (2006) Brd4 links chromatin targeting to HPV transcriptional silencing. Genes Dev 20:2383–2396

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wu S-Y, Lee A-Y, Lai H-T, Zhang H, Chiang C-M (2013) Phospho switch triggers Brd4 chromatin binding and activator recruitment for gene-specific targeting. Mol Cell 49:843–857

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wyspianska B, Bannister A, Barbieri I, Nangalia J, Godfrey A, Calero-Nieto F, Robson S, Rioja I, Li J, Wiese M, Cannizzaro E, Dawson M, Huntly B, Prinjha R, Green A, Gottgens B, Kouzarides T (2013) BET protein inhibition shows efficacy against JAK2V617F-driven neoplasms. Leukemia 28(1):88–97

    PubMed  Google Scholar 

  • Xi Q, Wang Z, Zaromytidou A-I, Zhang XH-F, Chow-Tsang L-F, Liu JX, Kim H, Barlas A, Manova-Todorova K, Kaartinen V, Studer L, Mark W, Patel DJ, Massague J (2011) A poised chromatin platform for TGF-B access to master regulators. Cell 147:1511–1524

    Google Scholar 

  • Yan J, Li Q, Lievens S, Tavernier J, You J (2010) Abrogation of the Brd4-positive transcription elongation factor b complex by papillomavirus E2 protein contributes to viral oncogene repression. J Virol 84(1):76–87

    PubMed Central  CAS  PubMed  Google Scholar 

  • Yang Z, Yik JHN, Chen R, He N, Jang MK, Ozato K, Zhou Q (2005) Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol Cell 19:535–545

    CAS  PubMed  Google Scholar 

  • Yap KL, Zhou M-M (2006) Structure and function of protein modules in chromatin biology. Results Probl Cell Differ 41:1–23

    CAS  PubMed  Google Scholar 

  • Yap KL, Li S, Munoz-Cabello AM, Raguz S, Zeng L, Mujtaba S, Gil J, Walsh MJ, Zhou M-M (2010) Molecular Interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Mol Cell 38(5):662–74; PubMed Central PMCID: PMC2886305

    Google Scholar 

  • You J, Li Q, Wu C, Kim J, Ottinger M, Howley PM (2009) Regulation of aurora B expression by the bromodomain protein Brd4. Mol Cell Biol 29(18):5094–5103

    PubMed Central  CAS  PubMed  Google Scholar 

  • Young RA (2011) Control of the embryonic stem cell state. Cell 144:940–954

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zeng L, Li J, Muller M, Yan S, Mujtaba S, Pan C, Wang Z, Zhou M-M (2005) Selective small molecules blocking HIV-1 Tat and coactivator PCAF association. J Amer Chem Soc 127:2376–2377

    CAS  Google Scholar 

  • Zeng L, Yap KL, Ivanov AV, Wang X, Mujtaba S, Plotnikova O III (2008) FJR, Zhou M-M. Structural insights into human KAP1 PHD finger-bromodomain and its role in gene silencing. Nat Struct Mol Biol 15(6):626–633

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zhang G, Liu R, Zhong Y, Plotnikov AN, Zhang W, Zeng L, Rusinova E, Gerona-Navarro G, Moshkina N, Joshua J, Chuang PY, Ohlmeyer M, He JC, Zhou M-M (2012) Down-regulation of NF-κB transcriptional activity in HIV-associated kidney disease by BRD4 inhibition. J Biol Chem 287(34):28840–28851; PubMed Central PMCID: PMC3436579

    Google Scholar 

  • Zhang G, Plotnikov AN, Rusinova E, Shen T, Morohashi K, Joshua J, Zeng L, Mujtaba S, Ohlmeyer M, Zhou M-M (2013) Structure-guided design of potent diazobenzene inhibitors for the BET bromodomains. J Med Chem 56:9251–9264

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zhao R, Nakamura T, Fu Y, Lazar Z, Spector DL (2011) Gene bookmarking accelerates the kinetics of post-mitotic transcriptional re-activation. Nat Cell Biol 13(11):1295–1304

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zhou M-M, Aggarwal AK, Verdin E, Ott M (2004) Inventors methods of identifying modulators of bromodomains. USA (2004)

    Google Scholar 

  • Zhou M, Huang K, Jung K-J, Cho W-K, Klase Z, Kashanchi F, Pise-Masison CA, Brady JN (2009) Bromodomain protein Brd4 regulates human immunodeficiency virus transcription through phosphorylation of CDK9 at threonine 29. J Virol 83(2):1036–1044

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zou JX, Revenko AS, Li LB, Gemo AT, Chen H-W (2007) ANCCA, an estrogen-regulated AAA+AT pase coactivator for ER-alpha, is required for coregulator occupancy and chromatin modification. Proc Natl Acad Sci USA 104(46):18067–18072

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zou JX, Guo L, Revenko AS, Tepper CG, Gemo AT, Kung H-J, Chen H-W (2009) Androgen-induced coactivator ANCCA mediates specific androgen receptor signaling in prostate cancer. Cancer Res 69(8):3339–3346

    CAS  PubMed  Google Scholar 

  • Zuber J, Shi J, Wang E, Rappaport AR, Herrmann H, Sison EA, Magoon D, Qi J, Blatt K, Wunderlich M, Taylor MJ, Johns C, Chicas A, Mulloy JC, Kogan SC, Brown P, Valent P, Bradner JE, Lowe SW, Vakoc CR (2011) RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 478:524–528; PubMed Central PMCID: PMC3328300

    Google Scholar 

Download references

Acknowledgments

We wish to acknowledge the members of the Zhou Group for helpful discussion. This work was supported in part by the research grants from the National Institutes of Health (to M.-M.Z.).

Author information

Authors and Affiliations

  1. Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Steven G. Smith & Ming-Ming Zhou

Authors
  1. Steven G. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ming-Ming Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ming-Ming Zhou .

Editor information

Editors and Affiliations

  1. Department of Structural & Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA

    Ming-Ming Zhou

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Smith, S.G., Zhou, MM. (2015). The Bromodomain as the Acetyl-Lysine Binding Domain in Gene Transcription. In: Zhou, MM. (eds) Histone Recognition. Springer, Cham. https://doi.org/10.1007/978-3-319-18102-8_1

Download citation

Publish with us

Policies and ethics

Search

Navigation