Print ISSN:-2581-3714

Online ISSN:-2581-3706


Current Issue

Year 2020

Volume: 5 , Issue: 2

  • Article highlights
  • Article tables
  • Article images

Article Access statistics

Viewed: 75

Emailed: 0

PDF Downloaded: 58

Samani, Sharma, Sharma, Manjunath PM, and Surendra V: Role of BRD4 in cancer – A review


Bromodomain 4 (BRD4) is the chromatin reader protein, belong to the family of Bromodomain and Extra Domain (BET). The BET family consist of BRD1, BRD2, BRD3, BRD4 and BRDT among all sub unit of bromodomain, BRD4 are responsible for pathogenesis when it get over expressed in the body. They interact directly on N-terminal of histones tail with acetylated lysine residue and keep the epigenetic regulation and promotes the normal gene expression. 1, 2 The BRD4 locates genomic areas to discrete through interactions with acetylated chromatin reader and regulates RNA polymerase-II through elongation and transcription factor directly on the mediator complex.3, 4 BRD4 keep oncogenic gene expression by direct interaction with acetylated transcription factor that includes RELA, ER, P53 and twist. 5, 6 normally BRD4 protein is needed to maintain chromatin stability to control the cell cycle, cell division, cell growth and cell proliferation in the healthy body. The in-vitro studies shows that heterozygous Brd4+/ mice have serious differentiation of cells and organogenesis abnormalities.7 Epigenetic regulation promotes the normal gene expression in the body by maintaining the chromatin reader. Epigenetic modifications are reversible changes to DNA that does not include a nucleotide sequence shift a range of epigenetic processes including changes in patterns of CPG island modifications in methylation and histone control gene keeping ordinary cellular homeostasis. Protein dysregulation responsible for communication and alteration of DNA macro molecular complexes and which promotes the notion of gene expression to that of epigenetic regulation and contributes to pathogenesis of disease. 8, 9

Functions of bromodomain and extra domain proteins on mammalian, herpesvirus associated with Kaposi sarcoma, INF, interferon, bovine papillomavirus, and human papillomaviruses

BET Protein (BRD2)


  1. Promotion of cells cycle.10, 11

  2. Closure of the embryos neural tube of the mouse.12, 13

  3. Maintenance of the neocortex number of GABAergic neurons and mice striatum.14

  4. Transcription assistance in hyper acetylated Chromatin (histone-chaperone property).15

  5. HOXA11and D11 transcriptional activation in  HEK293 cells 16

  6. Improvement of GATA1 activation in mediated erythroid gene.17

  7. HV LANA interact with mediated episomal Replication and viral genomic persistence18, 19

BET Protein (BRD3)


  1. Transcription assistance in hyper acetylated chromatin (histone chaperone property). 15

  2. Improvement of GATA1 activation mediated the erythroid gene. 17

  3. BRD3 nut fusion protein induced carcinogenesis.20

BET Protein (BRD4)


  1. Transition stimulation of G2/M in HELA cells.21

  2. Cell cycle continuation in P19 embryonic carcinoma cells.22

  3. Inner cell mass maintenance in mouse blastocyst.23

  4. NANOG transcriptional activation required to maintain ES cells pluripotency.24

  5. Release from a transcription elongation pause.25, 26

  6. Transcription assistance in hyper acetylated chromatin histone chaperone property.27

  7. Regulation of genes involved in mice’s learning and memory transcription.28

  8. Improvement of gene transcription induced by INF.29

  9. Cellular signal transducer response for oxidative stress.30

  10. Post mitotic gene bookmark for cell transcription reactivation.31, 32

  11. Protein BRD4 nut fusion induced carcinogenesis.20, 23

  12. KSHV LANA interact with mediated episomal replication and viral genomic survival.2, 33, 34

  13. KSHV LANA interaction mediating episomal replication and viral genomic survival 35, 33, 2

  14. Genome BPV binding to host mitotic chromosome.34

  15. E2 transcription control mediate and maintain genome DNA replication.36, 37, 38

BET Protein(BRDT)


  1. Transcription of gene regulation during spermatogenesis responsible for meiotic progression.39

  2. Machinery for splicing in testicular cells 40

  3. Remodeling of chromatin in cells.41, 42, 43

BRD-containing cancer proteins

BRD-containing proteins, deregulated in many cancer like breast cancer, colon cancer and stimulate and suppress malignant phenotypes expression.44

Effects of BRD4 cancer dysregulation

Bromodomain has BET protein family that was originally identified and play significant role in epigenetic regulation, BET proteins are frequently deregulated in cancer and lead to aberrant chromatin remodeling and tumorigenesis-mediated gene transcription.45, 46 A number of human cancers have reported where BRD4 over expression is one of the reason for genes mutations.47 BRD4 promotes the production of cell line metastasis in-vitro cell cycling, invasion, and cancer.48

Regulating of the cell cycle in cancer and non-cancer

BRD4 containing protein has significant role in cell cycle regulation and transcription in both cancer and non-cancer. the expression level of BRD4 indicate the function to control their expression in cell and their multiplication level in mitosis indicate cancer. 49 depletion of BRD4 results in aberrant mitosis with an abnormal occurrence of chromosomes to micronuclei and bridging chromosomes leading to cytokinesis failure and multilobulated nuclei.50 BRD4 significantly associated with mitotic chromosomes, and mitotic bookmark for early G1 phase in cell cycle qualities like Myc. 51, 52, 53

The transition from G1 phase to M phase in cell cycle rely on both BRD4’s chromatin decompaction related HAT activity and its kinase mediated transcription.54, 55 BRD4 with M / G1 phase in genes expression is correlated With the maintenance of high levels of chromatin acetylation during mitosis.52 the BRD4 brief isoform B, which is devoid of HAT activity, contributes to chromatin structure and chromothrypsis alterations. 56 BRD4 promotes their fast postmitotic transcription by binding to the transcription sites of M / G1 phase in cell cycle during genes expression. BRD4 depletion is therefore related with newly synthesized low production of RNAs of the M / G1 phase in gene expression.53

BRD4 offers transcriptional gene memory which is association through mitosis outcomes in rapid gene expression in the preceding cell cycle.57 Furthermore BRD4 was revealed to control G2 to M phase in cell cycle through its SPA 1 difference protein interaction. 58 SPA1 is generated in lymphocytes in reaction to mitogen activation.59 Ectopic SPA 1 also blocks the shift in HELA cells from G2 to M phase. BRD4 adjusts SPA 1 which relieves the barrier to the development of the cell cycle.58 Deletion of BRD4 in HELA cells arrests G1 phase in cell cycle while ectopic expression of BRD4 paradoxically gets inhibited.52, 53 Alternatively the depletion of BRD4 causes apoptosis.60 In both the reaction to DNA damage and oxidative stress, BRD4 was reported to result for aberrant stress reactions.61, 62

BRD4 differentiation and development in cell

BRD4 has great role in controlling cell cycle and promoting the cell growth, BRD4 is not only a general transcription factor but also about 10% of the gene regulatory components which are associated with both super enhancer and traditional promoters.63 BRD4 regulates genes expression and identify the status of the cell type as well as the cell cycle. 64, 63, 65 For instance, BRD4 has vital role in conservation of human and mouse embryonic stem cell identity.66 Differentiation reflects the down regulation of embryonic stem cell that relates genes such as OCT4 NANOG and PRDM14 and the up regulation of EMT related genes and Neuro-ectodermal differentiation. 66 BRD4 controls the expression of OCT4 genes silencing of BRD4 by either Short hairpin RNA or BET inhibitor treatment that allows the cells to accumulate in G1 phase of the cell cycle and gain cell morphology differentiation. 67

BRD4 is also needed for the re-expression of genes during MEF reprogramming to induced pluripotent stem cell.68 Reprogramming of C / EBP activated somatic B cells into induced pluripotent stem cells often relies on binding BRD4 to the super enhancers of the pluripotential gene that are likely to mediate chromatin remodeling and transcription.69

In the absence of BRD4, bone marrow stem cells cannot produce lymphoid stem cells, resulting in a failure to differentiate between B and T cells. 70 mature blood cells are not formed on OP9 culture due to depletion of human BRD4. 71 BRD4 Plays an important role in preserving cell identity whether stem cells or differentiated cells in line with its role in controlling the composition and transcription of chromatin.72

SSustained silencing of BRD4 in mice resulted in numerous developmental flaws among these skin hyperplasia, dysplasia and abnormal hair development and the loss of communities of secretory cells lysozyme.70 Where there is a correlation between chromatin hyper acetylation and BRD4 binding during spermatogenesis to active genes. In conjunction with chromatin condensation and loss of hyperacetylatedhistonesBRD4relocatestospermatidacrosomes during spermiogenesis.73 Latest laboratory trials show that the lack of BRD4 during early thymic growth leads to a significant loss of peripheral T cells.73

Initiation of BRD4 and transcription

Transcription initiation starts with the recruitment of RNA Polymerase II on the pre-initiation complex at the gene promoter region followed by serine 5 RNA polii phosphorylation and RNA poliipromoter interaction stabilization. The pre-initiation complex assembly is commonly affected by ENHS and are regulated by TFS and other regulatory proteins for transcription.74 RNA-Polymerase II has a transcription mediator which is a big modular organisation complex that translates signals from TFs and ENH and promoters, timing pre-initiation complex formation and initiation of transcription. 75, 76

Regulation on BRD4 and transcription

BRD4 contains 110 amino acid and recognized as a first protein that control cell cycle which are associated with chromosomes during mitosis to mark genes transcription in cell cycle in G1 phase.77, 78 BRD4 null mice die soon after implantation due to a lack of survival of the mass of the internal cell resulting in ESS.79 Through selective regulation of lineage specific genes. BRD4 is crucial for determining cell identity later during growth lee and collaborators using two conditional mouse knockout models have shown that adipogenesis and myogenesis require BRD4 expression. 80 The use of human fetal osteoblasts by najafowa et al proved that perturbation of activity impedes the entire cycle of osteoblast differentiation from early engagement to late mineralization and bone formation.81

Roles in gene regulation

BRDs containing proteins have various physiological functions either alone or as part of bigger protein complexes and most notably through transcription modulation that are engaged in gene regulation, first it is known that these proteins are engaged in regulatory chromatin changes that lead to chromatin remodeling and further histone modifications including acetylation and methylation. BRD containing proteins can also regulate transcription by specifically recognizing histones and by acting as scaffolds to control the recruitment of other chromatin transcription regulators, eventually the transcription machinery itself can be modulated.

Epigenetic regulation in the tumor microenvironment of BRD4 gene expression

Tumors consist of a heterogeneous cell that contains neoplastic tumor cells as well as non-neoplastic cells that produce the tumor microenvironment. The TME (tumor microenvironment) is made up of various kinds of cells including immune cells, fibroblasts inflammatory cells that are derived from the bone marrow and those of endothelial cells which promote the development of tumor blood vessels and continuous cellular signaling. The tumor cells recruited into the microenvironment within the TME (tumor microenvironment) collectively. The molecular signaling events occurring within the TME function to join the growth of tumors and allow cancer cells to obtain phenotypic characteristics such as improved invasion and migration that are critical to cancer metastasis growth.50, 69

Therapeutic strategies for targeting cancer with BET bromodomain proteins

Bromodomain is the family of BET protein which has important role in controlling biological mechanisms include inflammation and inflammatory disease. The dysregulation of BET proteins leads to the progression and metastatic activity in cancer cells.82 Importantly the maintenance of malignant phenotype in cancer cells in both hematopoietic and solid tumor cells depends on epigenetic deregulation.83 In addition human phase 1 clinical trials evaluating the safety and effectiveness of novel small molecule. BET inhibitors exhibit minimal and reversible clinical toxicity in patients with human cancer 84 both in-vitro and in-vivo studies. BET inhibitors has reported target inhibition and indicate prospective therapeutic impacts, but phase I clinical trials with BET inhibitors in patients with human cancer have not shown substantial therapeutic benefit.85

Bromodomain-inhibited processes and pathways in cancer

BRD proteins affect the regulation of essential oncogenes in tumor cells, such as Myc. BRD’s pharmacological inhibition offers better ways of targeting and manipulating key pathways such as Janus kinase / signal transducer, transcription activator (JAK / STAT) and kappa light. The polypeptide gene enhancer nuclear factor (NF-kB) in B Cells has mechanistic signals inhibitors activity which is activated by BRD4 displacement in regions of super enhancers that are massive clusters of gene expression as compared to the few hundred bases covered by standard enhancer regions the super enhancers regions occupy up to 50 kb that exist in oncogenes and tumor progression related genes.86, 87

Figure 1

Extra terminal Bromodomain (BRD) inhibition displaces BRD4 from super enhancers regions. Inhibition of BRDs by small molecules effectively displaces BRD4 from these super enhancer regions compared to normal enhancer regions, thereby allowing oncogenes to be specifically targeted.

Importance of BRD4 in cancer

BRD4 containing protein has play significant role in elongation and transcription in both normal cell and cancerous cell. The increases rate of BRD4 expression in normal cell lead to cancerous cell because of its ability to form fusion proteins with other nuclear proteins which suggest that BRD4 has great role in the development of cancer, the NUT carcinoma midline is active human cancer arising from nuclear protein in the gene for testis.88, 89 BRD4 overexpression was found to be associated with poor prognosis in patients with liver cancer. BRD4 over-expression facilitates hepatocellular carcinoma cell growth and invasion90 among melanoma tissues, BRD4 is significantly higher than melanocytes. 91


Bromodomain (BRD4) consist of 110 amino acid domain protein and belongs to the chromatin reader protein that has BET family which include BRD1, BRD2, BRD3, BRD4 and BRDT. Normally All bet family are present in the body for their specific function but when they over expressed in the body they lead to cause disease pathogenesis but among all the bet family most challenging bromodomain protein is BRD4 which interact with acetylated lysine residue at N-terminal of histone tail in presence of acetyltransferase enzyme for epigenetic regulation such as cell division, cell proliferation, cell growth and maintain cellular mechanism but dysregulation of BRD4 due to mutation leads to the progression and metastatic activity in cancer cells, many inhibitor are designed and synthesized for the inhibition of bromodomain (BRD4) but none of them show good pharmacological activity due to poor selectivity and poor therapy The main reason for improper inhibition of bromodomain is that it doesn’t identify the bet family properly during targeting of bromodomain protein therefore it doesn’t have clear mechanism of action.


I express thank to my father Mr. Samsulhak Miya and Mother Ms. Jaisul Nesha for consistent love and encouragement. I am grateful to Principal and Management of Acharya & BM Reddy College of Pharmacy, Bengaluru, for extending their cooperation and providing us with necessary support for the preparing of this review article.

Source of Finding


Conflict of Interest




Christophe Dhalluin Justin E. Carlson Lei Zeng Cheng He Aneel K. Aggarwal Ming-Ming Zhou Structure and ligand of a histone acetyltransferase bromodomainNature199939967354916


Panagis Filippakopoulos Sarah Picaud Maria Mangos Tracy Keates Jean-Philippe Lambert Dalia Barsyte-Lovejoy Histone Recognition and Large-Scale Structural Analysis of the Human Bromodomain FamilyCell2012149121431


Moon Kyoo Jang Kazuki Mochizuki Meisheng Zhou Ho-Sang Jeong John N. Brady Keiko Ozato The Bromodomain Protein Brd4 Is a Positive Regulatory Component of P-TEFb and Stimulates RNA Polymerase II-Dependent TranscriptionMolecular Cell200519452334


Zhiyuan Yang Jasper H.N. Yik Ruichuan Chen Nanhai He Moon Kyoo Jang Keiko Ozato Recruitment of P-TEFb for Stimulation of Transcriptional Elongation by the Bromodomain Protein Brd4Molecular Cell200519453545


J Shi Y Wang L Zeng Y Wu Disrupting the interaction of BRD4 with diacetylated Twist suppresses tumorigenesis in basal-like breast cancerCancer cell201425221025


Helen Jayne Susan Stewart Gillian Abigail Horne Sarah Bastow Timothy James Telfer Chevassut BRD4 associates with p53 in DNMT3A-mutated leukemia cells and is implicated in apoptosis by the bromodomain inhibitor JQ1Cancer Medicine20132682635


M R Schweiger Brd4-independent transcriptional repression function of the papillomavirus e2 proteinsJ Virol20078118961222


R. Prinjha A. Tarakhovsky Chromatin targeting drugs in cancer and immunityGenes & Development2013271617318


D. Bayarsaihan Epigenetic Mechanisms in InflammationJ Dent Res2011901917


G V Denis C Vaziri N Guo D V Faller RING3 kinase transactivates promoters of cell cycle regulatory genes through E2FCell Growth Differ20001141724


G V Denis M E Mccomb D V Faller A Sinha P B Romesser C E Costello Identification of transcription complexes that contain the double bromodomain protein Brd2 and chromatin remodeling machinesJ Proteome Res2006550211


Enyuan Shang Xiangyuan Wang Duancheng Wen David A. Greenberg Debra J. Wolgemuth Double bromodomain-containing gene Brd2 is essential for embryonic development in mouseDevelopmental Dynamics2009238490817


Aron Gyuris Diana J. Donovan Kimberly A. Seymour Lindsay A. Lovasco Nathaniel R. Smilowitz Anthony L.P. Halperin Jan E. Klysik Richard N. Freiman The chromatin-targeting protein Brd2 is required for neural tube closure and embryogenesisBiochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms20091789541321


Libor Velíšek Enyuan Shang Jana Velíšková Tamar Chachua Stephania Macchiarulo Giorgi Maglakelidze GABAergic Neuron Deficit As An Idiopathic Generalized Epilepsy Mechanism: The Role Of BRD2 Haploinsufficiency In Juvenile Myoclonic EpilepsyPLoS ONE201168e23656


Gary LeRoy Brenden Rickards S.J. Flint The Double Bromodomain Proteins Brd2 and Brd3 Couple Histone Acetylation to TranscriptionMolecular Cell20083015160


Gary LeRoy Iouri Chepelev Peter A DiMaggio Mario A Blanco Barry M Zee Keji Zhao Proteogenomic characterization and mapping of nucleosomes decoded by Brd and HP1 proteinsMol Cell 20123068


Aaron J. Stonestrom Sarah C. Hsu Kristen S. Jahn Peng Huang Cheryl A. Keller Belinda M. Giardine Functions of BET proteins in erythroid gene expressionBlood201512518282534


Georgina M. Platt Guy R. Simpson Sibylle Mittnacht Thomas F. Schulz Latent Nuclear Antigen of Kaposi’s Sarcoma-Associated Herpesvirus Interacts with RING3, a Homolog of theDrosophila Female Sterile Homeotic (fsh) GeneJ Virol19997312978995


Abel Viejo-Borbolla Matthias Ottinger Eva Brüning Antje Bürger Regina König Emrah Kati Brd2/RING3 Interacts with a Chromatin-Binding Domain in the Kaposi's Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen 1 (LANA-1) That Is Required for Multiple Functions of LANA-1J Virology2005791361829


C A French C L Ramirez J Kolmakova T T Hickman M J Cameron BRD-NUT oncoproteins:A family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cellsOncogene200827223742


A Dey J Ellenberg A Farina A E Coleman T Maruyama bromodomain protein, MCAP, associates with mitotic chromosomes and affects G2-to-M transitionMol Cell Biol200020653749


A. Dey F. Chitsaz A. Abbasi T. Misteli K. Ozato The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosisProc National Acad Sci200310015875863


Denis Houzelstein Simon L. Bullock Denise E. Lynch Elena F. Grigorieva Valerie A. Wilson Rosa S. P. Beddington Growth and Early Postimplantation Defects in Mice Deficient for the Bromodomain-Containing Protein Brd4Molecular Cell Biol2002221137943802


W Liu P Stein X Cheng W Yang N-Y Shao E E Morrisey BRD4 regulates Nanog expression in mouse embryonic stem cells and preimplantation embryosCell Death Differ20142112195060


Moon Kyoo Jang Kazuki Mochizuki Meisheng Zhou Ho-Sang Jeong John N. Brady Keiko Ozato The Bromodomain Protein Brd4 Is a Positive Regulatory Component of P-TEFb and Stimulates RNA Polymerase II-Dependent TranscriptionMolecular Cell200519452334


W Liu Q Ma K Wong W Li Brd4 and JMJD6-associated anti-pause enhancers in regulation of transcriptional pause releaseCell201315515811595


T Kanno Y Kanno G Leroy E Campos BRD4 assists elongation of both coding and enhancer RNAs by interacting with acetylated histonesNat Struct Mol Biol201421104757


Erica Korb Margo Herre Ilana Zucker-Scharff Robert B Darnell C David Allis BET protein Brd4 activates transcription in neurons and BET inhibitor Jq1 blocks memory in miceNat Neurosci20151810146473


M. C. Patel M. Debrosse M. Smith A. Dey W. Huynh N. Sarai BRD4 Coordinates Recruitment of Pause Release Factor P-TEFb and the Pausing Complex NELF/DSIF To Regulate Transcription Elongation of Interferon-Stimulated GenesMolecular Cell Biol2013331224972507


M Hussong S T Börno M Kerick A Wunderlich A Franz H Sültmann The bromodomain protein BRD4 regulates the KEAP1/NRF2-dependent oxidative stress responseCell Death Dis2014541195


Anup Dey Akira Nishiyama Tatiana Karpova James McNally Keiko Ozato Brd4 Marks Select Genes on Mitotic Chromatin and Directs Postmitotic TranscriptionMol Biol Cell2009202348994909


Rui Zhao Tetsuya Nakamura Yu Fu Zsolt Lazar David L. Spector Gene bookmarking accelerates the kinetics of post-mitotic transcriptional re-activationNatur Cell Biol2011131112951304


M Ottinger T Christalla K Nathan M M Brinkmann 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 arrestJ Virol2006801077286


Jianxin You Jennie L Croyle Akiko Nishimura Keiko Ozato Peter M Howley Interaction of the Bovine Papillomavirus E2 Protein with Brd4 Tethers the Viral DNA to Host Mitotic ChromosomesCell2004117334960


Jianxin You Viswanathan Srinivasan Gerald V. Denis William J. Harrington Mary E. Ballestas Kenneth M. Kaye Kaposi's Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen Interacts with Bromodomain Protein Brd4 on Host Mitotic ChromosomesJ Virol20068018890919


S Y Wu A Y Lee S Y Hou J K Kemper Brd4 links chromatin targeting to HPV transcriptional silencingGenes Dev200620238396


Michal-Ruth Schweiger Jianxin You Peter M. Howley Bromodomain Protein 4 Mediates the Papillomavirus E2 Transcriptional Activation FunctionJ Virol2006809427685


M. G. McPhillips J. G. Oliveira J. E. Spindler R. Mitra A. A. McBride Brd4 Is Required for E2-Mediated Transcriptional Activation but Not Genome Partitioning of All PapillomavirusesJ Virol20068019953043


J Gaucher F Boussouar E Montellier S Curtet Bromodomain-dependent stage-specific male genome programming by BrdtEMBOJ201231380920


Binyamin D. Berkovits Li Wang Paolo Guarnieri Debra J. Wolgemuth The testis-specific double bromodomain-containing protein BRDT forms a complex with multiple spliceosome components and is required for mRNA splicing and 3′-UTR truncation in round spermatidsNucleic Acids Res20124015716275


Surbhi Dhar Anusha Thota Manchanahalli Rangaswamy Satyanaray Rao Insights into Role of Bromodomain, Testis-specific (Brdt) in Acetylated Histone H4-dependent Chromatin Remodeling in Mammalian SpermiogenesisJ Biol Chem2012287963876405


Christophe Pivot-Pajot Cécile Caron Jérôme Govin Alexandre Vion Sophie Rousseaux Saadi Khochbin Acetylation-Dependent Chromatin Reorganization by BRDT, a Testis-Specific Bromodomain-Containing ProteinMol Cell Biol20032315535465


K. Sasaki T. Ito N. Nishino S. Khochbin M. Yoshida Real-time imaging of histone H4 hyperacetylation in living cellsProce National Acad Sci2009106381625762


Susanne Muller Panagis Filippakopoulos Stefan Knapp Bromodomains as therapeutic targetsExpert Rev Mol Med20111329


Jude T. Deeney Anna C. Belkina Orian S. Shirihai Barbara E. Corkey Gerald V. Denis BET Bromodomain Proteins Brd2, Brd3 and Brd4 Selectively Regulate Metabolic Pathways in the Pancreatic β-CellPLOS ONE2016113e0151329


I Marazzi Chromatin dependencies in cancer and inflammationNat Rev Mol Cell Biol201819424561


James E. Bradner Denes Hnisz Richard A. Young Transcriptional Addiction in CancerCell2017168462943


C A French Small-Molecule Targeting of BET Proteins in CancerAdv Cancer Res20161312158


Z Yang N He Q Zhou Brd4 recruits P-TEFb to chromosomes at late mitosis to promote G1 gene expression and cell cycle progressionMol Cell Biol20082896776


Jianxin You Qing Li Chong Wu Jina Kim Matthias Ottinger Peter M. Howley Regulation of Aurora B Expression by the Bromodomain Protein Brd4Mol Cell Biol2009291850945103


A Dey J Ellenberg A Farina A E Coleman A bromodomain protein, MCAP, associates with mitotic chromosomes and affects G(2)-to-M transitionMol Cell Biol200020653749


Anup Dey Akira Nishiyama Tatiana Karpova James McNally Keiko Ozato Brd4 Marks Select Genes on Mitotic Chromatin and Directs Postmitotic TranscriptionMolecul Biol Cell2009202348994909


Kazuki Mochizuki Akira Nishiyama Moon Kyoo Jang Anup Dey Anu Ghosh Tomohiko Tamura The Bromodomain Protein Brd4 Stimulates G1Gene Transcription and Promotes Progression to S PhaseJ Biol Chem20082831490408


B. N. Devaiah B. A. Lewis N. Cherman M. C. Hewitt B. K. Albrecht P. G. Robey BRD4 is an atypical kinase that phosphorylates Serine2 of the RNA Polymerase II carboxy-terminal domainProcee National Acad Sci201210918692732


Ballachanda N Devaiah Chanelle Case-Borden Anne Gegonne Chih Hao Hsu Qingrong Chen Daoud Meerzaman BRD4 is a histone acetyltransferase that evicts nucleosomes from chromatinNature Structural Mol Biol20162365408


S R Floyd M E Pacold Q Huang S M Clarke The bromodomain protein Brd4 insulates chromatin from DNA damage signallingNature201349824650


Rui Zhao Tetsuya Nakamura Yu Fu Zsolt Lazar David L. Spector Gene bookmarking accelerates the kinetics of post-mitotic transcriptional re-activationNature Cell Biol2011131112951304


Andrea Farina Masakazu Hattori Jun Qin Yoshihiro Nakatani Nagahiro Minato Keiko Ozato Bromodomain Protein Brd4 Binds to GTPase-Activating SPA-1, Modulating Its Activity and Subcellular LocalizationMolecul Cellul Biol20042420905969


H Kurachi Y Wada N Tsukamoto M Maeda Human SPA-1 gene product selectively expressed in lymphoid tissues is a specific GTPase-activating protein for Rap1 and Rap2. Segregate expression profiles from a rap1GAP gene productJ Biol Chem19972722808188


Tetsuo Maruyama Andrea Farina Anup Dey JaeHun Cheong Vladimir P. Bermudez Tomohiko Tamura A Mammalian Bromodomain Protein, Brd4, Interacts with Replication Factor C and Inhibits Progression to S PhaseMol Cell Biol20022218650920


N. Tasdemir A. Banito J.-S. Roe D. Alonso-Curbelo M. Camiolo D. F. Tschaharganeh BRD4 Connects Enhancer Remodeling to Senescence Immune SurveillanceCancer Disc20166661229


M Hussong S T Börno M Kerick A Wunderlich A Franz H Sültmann The bromodomain protein BRD4 regulates the KEAP1/NRF2-dependent oxidative stress responseCell Death Dis201454e1195


Warren A. Whyte David A. Orlando Denes Hnisz Brian J. Abraham Charles Y. Lin Michael H. Kagey Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity GenesCell2013153230719


J Loven H A Hoke C Y Lin A Lau Selective inhibition of tumor oncogenes by disruption of super-enhancersCell201315332034


J D Brown C Y Lin Q Duan G Griffin NF-kB directs dynamic super enhancer formation in inflammation and atherogenesisMol Cell20145621931


Raffaella Di Micco Barbara Fontanals-Cirera Vivien Low Panagiotis Ntziachristos Stephanie K. Yuen Claudia D. Lovell Control of Embryonic Stem Cell Identity by BRD4-Dependent Transcriptional Elongation of Super-Enhancer-Associated Pluripotency GenesCell Reps20149123447


Tao Wu Hugo Borges Pinto Yasunao F. Kamikawa Mary E. Donohoe The BET Family Member BRD4 Interacts with OCT4 and Regulates Pluripotency Gene ExpressionStem Cell Reports201543390403


L Liu Y Xu M He M Zhang Transcriptional pause release is a rate-limiting step for somatic cell reprogrammingCell Stem Cell20141557488


Di Stefano B Collombet S Jakobsen J S Wierer M C/EBPa creates elite cells for iPSC reprogramming by upregulating Klf4 and increasing the levels of Lsd1 and Brd4Nat Cell Biol20161837181


Jessica E. Bolden Nilgun Tasdemir Lukas E. Dow Johan H. van Es John E. Wilkinson Zhen Zhao Inducible In Vivo Silencing of Brd4 Identifies Potential Toxicities of Sustained BET Protein InhibitionCell Rep201486191929


R M Rodriguez B Suarez-Alvarez R Salvanes C Huidobro Role of BRD4 in hematopoietic differentiation of embryonic stem cellsEpigenetics2014956678


Denis Houzelstein Simon L. Bullock Denise E. Lynch Elena F. Grigorieva Valerie A. Wilson Rosa S. P. Beddington Growth and Early Postimplantation Defects in Mice Deficient for the Bromodomain-Containing Protein Brd4Mol Cell Biol2002221137943802


Jessica M Bryant Shelley L Berger Low-hanging fruit: targeting Brdt in the testesEMBO J2012311937889


Iris Jonkers John T. Lis Getting up to speed with transcription elongation by RNA polymerase IINature Rev Mol Cell Biol201516316777


Benjamin L. Allen Dylan J. Taatjes The Mediator complex: a central integrator of transcriptionNature Rev Mol Cell Biol201516315566


Raymond J. Kelleher Peter M. Flanagan Roger D. Kornberg A novel mediator between activator proteins and the RNA polymerase II transcription apparatusCell1990617120915


A Dey J Ellenberg A Farina A E Coleman T Maruyama S Sciortino A bromodomain protein, MCAP, associates with mitotic chromosomes and effects, G(2)-to-M transitionMol Cell Biol200020653786


Z Y Yang N H He Q Zhou Brd4 recruits P-TER to chromosomes at late mitosis to promote G(1) gene expression and cell cycle progressionMol Cell Biol20082896776


Denis Houzelstein Simon L. Bullock Denise E. Lynch Elena F. Grigorieva Valerie A. Wilson Rosa S. P. Beddington Growth and Early Postimplantation Defects in Mice Deficient for the Bromodomain-Containing Protein Brd4Mol Cell Biol2002221137943802


J E Lee Y K Park S Park Y Jang Brd4 binds to active enhancers to control cell identity gene induction in adipogenesis and myogenesisNat Commun201782217


Zeynab Najafova Roberto Tirado-Magallanes Malayannan Subramaniam Tareq Hossan Geske Schmidt Sankari Nagarajan BRD4 localization to lineage-specific enhancers is associated with a distinct transcription factor repertoireNucleic Acids Res201745112741


Sergei I. Grivennikov Florian R. Greten Michael Karin Immunity, Inflammation, and CancerCell2010140688399


J S Roe BET Bromodomain Inhibition Suppresses the Function of Hematopoietic Transcription Factors in Acute Myeloid LeukemiaMol Cell2015586102867


M Boi The BET Bromodomain Inhibitor OTX015 Affects Pathogenetic Pathways in Preclinical B-cell Tumor Models and Synergizes with Targeted DrugsClin Cancer Res2015217162866


Anastasios Stathis Francesco Bertoni BET Proteins as Targets for Anticancer TreatmentCancer Disc2018812436


W A Whyte Master transcription factors and mediator establish superenhancers at key cell identity genesCell201315330719


Sebastian Pott Jason D Lieb What are super-enhancers?Nature Genetics2015471812


P Zhang BRD4 promotes tumor growth and epithelial-mesenchymal transition in hepatocellular carcinomaInt J Immuno Pathol Pharmacol2015283644


M F Segura BRD4 sustains melanoma proliferation and represents a new target for epigenetic therapyCancer Res201373626476


C A French BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinomaCancer Res2003633047


C A French NUT midline carcinomaCancer Genet Cytogenet20102031620


© 2020 Published by Innovative Publication Creative Commons Attribution - NonCommercial 4.0 International (CC BY-NC 4.0) license (