Place your BETs: the therapeutic potential of bromodomains.

Therapeutic targeting of the processes that regulate histone modification is a growing area of scientific exploration. Although most interest has concentrated on the various families of enzymes that contribute to these processes, this review focuses on emerging data demonstrating the chemical tractability and therapeutic potential of a hitherto underexplored family of proteins, namely the bromodomain (BRD) family of reader proteins. These proteins perform a crucial role in translating histone modifications with powerful transcriptional consequences. We review current knowledge of the biology of this emergent target class and highlight recent breakthroughs that now make the BRD family of reader proteins attractive for drug discovery.

[1]  D. Blackwood,et al.  Evidence implicating BRD1 with brain development and susceptibility to both schizophrenia and bipolar affective disorder , 2006, Molecular Psychiatry.

[2]  P. Evans,et al.  The structural basis for the recognition of acetylated histone H4 by the bromodomain of histone acetyltransferase Gcn5p , 2000, The EMBO journal.

[3]  A. Hoffmann,et al.  A Unifying Model for the Selective Regulation of Inducible Transcription by CpG Islands and Nucleosome Remodeling , 2009, Cell.

[4]  William B. Smith,et al.  Selective inhibition of BET bromodomains , 2010, Nature.

[5]  Robert D Cardiff,et al.  E mu-BRD2 transgenic mice develop B-cell lymphoma and leukemia. , 2004, Blood.

[6]  Joel P. Mackay,et al.  Structural Basis and Specificity of Acetylated Transcription Factor GATA1 Recognition by BET Family Bromodomain Protein Brd3 , 2011, Molecular and Cellular Biology.

[7]  Andrew J. Bannister,et al.  Histone Methylation Dynamic or Static? , 2002, Cell.

[8]  R. Vaughan,et al.  Genes associated with rheumatoid arthritis and mild inflammatory arthritis. I. Major histocompatibility complex class I, II, and III allotypes. , 1990, Annals of the rheumatic diseases.

[9]  A. Mushegian,et al.  Prp8, the pivotal protein of the spliceosomal catalytic center, evolved from a retroelement-encoded reverse transcriptase. , 2011, RNA.

[10]  Yuanyu Hu,et al.  Chromatin-remodelling factor BRG1 selectively activates a subset of interferon-alpha-inducible genes. , 2002, Nature cell biology.

[11]  N. Crawford,et al.  Bromodomain 4 activation predicts breast cancer survival , 2008, Proceedings of the National Academy of Sciences.

[12]  Tariq Ahmad,et al.  Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci , 2010, Nature Genetics.

[13]  E. Brambilla,et al.  Functional characterization of ATAD2 as a new cancer/testis factor and a predictor of poor prognosis in breast and lung cancers , 2010, Oncogene.

[14]  E. Seto,et al.  HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention , 2007, Oncogene.

[15]  M. Itokawa,et al.  Involvement of SMARCA2/BRM in the SWI/SNF chromatin-remodeling complex in schizophrenia. , 2009, Human molecular genetics.

[16]  L. Velíšek,et al.  GABAergic Neuron Deficit As An Idiopathic Generalized Epilepsy Mechanism: The Role Of BRD2 Haploinsufficiency In Juvenile Myoclonic Epilepsy , 2011, PloS one.

[17]  J. Archambault,et al.  Proteasomal Degradation of the Papillomavirus E2 Protein Is Inhibited by Overexpression of Bromodomain-Containing Protein 4 , 2009, Journal of Virology.

[18]  Qiang Zhou,et al.  Isolation and functional characterization of P-TEFb-associated factors that control general and HIV-1 transcriptional elongation. , 2011, Methods.

[19]  S. Purcell,et al.  Support of association between BRD1 and both schizophrenia and bipolar affective disorder , 2010, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[20]  Y. Wan,et al.  Chromatin remodeling complex in Treg function. , 2009, International immunopharmacology.

[21]  C. French.  NUT midline carcinoma , 2014, Nature Reviews Cancer.

[22]  T. Kouzarides.  Chromatin Modifications and Their Function , 2007, Cell.

[23]  Ming-Ming Zhou,et al.  A small molecule binding to the coactivator CREB-binding protein blocks apoptosis in cardiomyocytes. , 2011, Chemistry & biology.

[24]  P. Howley,et al.  Kaposi's Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen Interacts with Bromodomain Protein Brd4 on Host Mitotic Chromosomes , 2006, Journal of Virology.

[25]  S. Smale.  Selective Transcription in Response to an Inflammatory Stimulus , 2010, Cell.

[26]  R. Medzhitov,et al.  Control of Inducible Gene Expression by Signal-Dependent Transcriptional Elongation , 2009, Cell.

[27]  Keji Zhao,et al.  Rapid and Phosphoinositol-Dependent Binding of the SWI/SNF-like BAF Complex to Chromatin after T Lymphocyte Receptor Signaling , 1998, Cell.

[28]  M. Marin,et al.  Implication of the Lymphocyte-Specific Nuclear Body Protein Sp140 in an Innate Response to Human Immunodeficiency Virus Type 1 , 2002, Journal of Virology.

[29]  M. Ikeda,et al.  Association study of bromodomain‐containing 1 gene with schizophrenia in Japanese population , 2009, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[30]  Kairong Cui,et al.  The Chromatin-Remodeling BAF Complex Mediates Cellular Antiviral Activities by Promoter Priming , 2004, Molecular and Cellular Biology.

[31]  Andrew J. Bannister,et al.  Regulation of chromatin by histone modifications , 2011, Cell Research.

[32]  R. Cardiff,et al.  ANCCA/ATAD2 overexpression identifies breast cancer patients with poor prognosis, acting to drive proliferation and survival of triple-negative cells through control of B-Myb and EZH2. , 2010, Cancer research.

[33]  T. Chi.  A BAF-centred view of the immune system , 2004, Nature Reviews Immunology.

[34]  S. Knapp,et al.  3,5-Dimethylisoxazoles Act As Acetyl-lysine-mimetic Bromodomain Ligands , 2011, Journal of medicinal chemistry.

[35]  K. Jones,et al.  The multi-tasking P-TEFb complex. , 2008, Current opinion in cell biology.

[36]  P. Bamborough,et al.  Discovery and characterization of small molecule inhibitors of the BET family bromodomains. , 2011, Journal of medicinal chemistry.

[37]  R. Young,et al.  BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc , 2011, Cell.

[38]  E. Nestler,et al.  Epigenetics in the Nervous System , 2008, The Journal of Neuroscience.

[39]  T. Schulz,et al.  WHAT do viruses BET on? , 2010, Frontiers in bioscience.

[40]  Shwu‐Yuan Wu,et al.  The Double Bromodomain-containing Chromatin Adaptor Brd4 and Transcriptional Regulation* , 2007, Journal of Biological Chemistry.

[41]  A. Granito,et al.  PML Nuclear Body Component Sp140 Is a Novel Autoantigen in Primary Biliary Cirrhosis , 2010, The American Journal of Gastroenterology.

[42]  L. Staudt,et al.  The biology of human lymphoid malignancies revealed by gene expression profiling. , 2005, Advances in immunology.

[43]  S. Imbeaud,et al.  SMARCA2 and other genome-wide supported schizophrenia-associated genes: regulation by REST/NRSF, network organization and primate-specific evolution. , 2010, Human molecular genetics.

[44]  J. Manfredi,et al.  Target structure-based discovery of small molecules that block human p53 and CREB binding protein association. , 2006, Chemistry & biology.

[45]  Lei Zeng,et al.  Structure and ligand of a histone acetyltransferase bromodomain , 1999, Nature.

[46]  C. Rice,et al.  Suppression of inflammation by a synthetic histone mimic , 2010, Nature.

[47]  C. French.  NUT midline carcinoma. , 2010, Cancer genetics and cytogenetics.

[48]  C. Allis,et al.  Translating the Histone Code , 2001, Science.

[49]  Jonathan Cohen.  The immunopathogenesis of sepsis , 2002, Nature.

[50]  Mark A. Dawson,et al.  Inhibition of BET Recruitment to Chromatin As An Effective Treatment for MLL-Fusion Leukaemia , 2011 .

[51]  J. Ziegler,et al.  Hepatic Veno-Occlusive Disease with Immunodeficiency , 2013 .

[52]  R. M. Simpson,et al.  Deletion of the proline-rich region of the murine metastasis susceptibility gene Brd4 promotes epithelial-to-mesenchymal transition- and stem cell-like conversion. , 2011, Cancer research.

[53]  A. Belkina,et al.  Obesity genes and insulin resistance. , 2010, Current opinion in endocrinology, diabetes, and obesity.

[54]  J. G. Oliveira,et al.  Brd4: tethering, segregation and beyond. , 2004, Trends in microbiology.

[55]  G. Denis.  Bromodomain coactivators in cancer, obesity, type 2 diabetes, and inflammation. , 2010, Discovery medicine.

[56]  R. Hardison,et al.  Bromodomain protein Brd3 associates with acetylated GATA1 to promote its chromatin occupancy at erythroid target genes , 2011, Proceedings of the National Academy of Sciences of the United States of America.

[57]  Edwin Smith,et al.  The Language of Histone Crosstalk , 2010, Cell.

[58]  Lars Alfredsson,et al.  Specific interaction between genotype, smoking and autoimmunity to citrullinated α-enolase in the etiology of rheumatoid arthritis , 2009, Nature Genetics.

[59]  Thomas L. Rothstein,et al.  Eμ-BRD2 transgenic mice develop B-cell lymphoma and leukemia , 2004 .

[60]  S. Lowe,et al.  RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia , 2011, Nature.

[61]  Jeroen Krijgsveld,et al.  Cooperative binding of two acetylation marks on a histone tail by a single bromodomain , 2009, Nature.

[62]  Adrian Bird,et al.  Perceptions of epigenetics , 2007, Nature.

[63]  Kairong Cui,et al.  A novel genetic strategy reveals unexpected roles of the Swi–Snf–like chromatin-remodeling BAF complex in thymocyte development , 2008, The Journal of experimental medicine.

[64]  Jennifer A. Smith,et al.  The Brd4 Extraterminal Domain Confers Transcription Activation Independent of pTEFb by Recruiting Multiple Proteins, Including NSD3 , 2011, Molecular and Cellular Biology.

[65]  Scott A. Armstrong,et al.  MLL translocations, histone modifications and leukaemia stem-cell development , 2007, Nature Reviews Cancer.

[66]  K. Helin,et al.  ATAD2 is a novel cofactor for MYC, overexpressed and amplified in aggressive tumors. , 2009, Cancer research.

[67]  Ming-Ming Zhou,et al.  Selective small molecules blocking HIV-1 Tat and coactivator PCAF association. , 2005, Journal of the American Chemical Society.

[68]  I B Dawid,et al.  The bromodomain: a conserved sequence found in human, Drosophila and yeast proteins. , 1992, Nucleic acids research.

[69]  Ming-Ming Zhou,et al.  Brd4 Coactivates Transcriptional Activation of NF-κB via Specific Binding to Acetylated RelA , 2008, Molecular and Cellular Biology.

[70]  C. Benkelfat,et al.  Association study of the trinucleotide repeat polymorphism within SMARCA2 and schizophrenia , 2006, BMC Genetics.

[71]  Guy Pratt,et al.  A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia , 2008, Nature Genetics.

[72]  T. Mahmoudi,et al.  Conserved P-TEFb-interacting domain of BRD4 inhibits HIV transcription , 2007, Proceedings of the National Academy of Sciences.

[73]  Roberto Sanchez,et al.  The role of human bromodomains in chromatin biology and gene transcription. , 2009, Current opinion in drug discovery & development.

[74]  P. Howley,et al.  Interaction of the Bovine Papillomavirus E2 Protein with Brd4 Tethers the Viral DNA to Host Mitotic Chromosomes , 2004, Cell.

[75]  E. Seemanová,et al.  DNA sequencing of CREBBP demonstrates mutations in 56% of patients with Rubinstein–Taybi syndrome (RSTS) and in another patient with incomplete RSTS , 2005, Human Genetics.

[76]  S. M. de la Monte,et al.  Identification and Characterization of a Leukocyte-specific Component of the Nuclear Body* , 1996, The Journal of Biological Chemistry.

[77]  P. Greengard,et al.  Epigenetic mechanisms of mental retardation. , 2011, Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques.

[78]  A. Revenko,et al.  Chromatin Loading of E2F-MLL Complex by Cancer-Associated Coregulator ANCCA via Reading a Specific Histone Mark , 2010, Molecular and Cellular Biology.

[79]  G. Denis,et al.  An emerging role for bromodomain‐containing proteins in chromatin regulation and transcriptional control of adipogenesis , 2010, FEBS letters.

[80]  Z. Klase,et al.  Bromodomain Protein Brd4 Regulates Human Immunodeficiency Virus Transcription through Phosphorylation of CDK9 at Threonine 29 , 2008, Journal of Virology.

[81]  A. Tarakhovsky,et al.  Tools and landscapes of epigenetics , 2010, Nature Immunology.

[82]  J. Ziegler,et al.  Mutations in the gene encoding the PML nuclear body protein Sp110 are associated with immunodeficiency and hepatic veno-occlusive disease , 2006, Nature Genetics.