title: BRD4 localization to lineage-specific enhancers is associated with a distinct transcription factor repertoire.
abstract: Proper temporal epigenetic regulation of gene expression is essential for cell fate determination and tissue development. The Bromodomain-containing Protein-4 (BRD4) was previously shown to control the transcription of defined subsets of genes in various cell systems. In this study we examined the role of BRD4 in promoting lineage-specific gene expression and show that BRD4 is essential for osteoblast differentiation. Genome-wide analyses demonstrate that BRD4 is recruited to the transcriptional start site of differentiation-induced genes. Unexpectedly, while promoter-proximal BRD4 occupancy correlated with gene expression, genes which displayed moderate expression and promoter-proximal BRD4 occupancy were most highly regulated and sensitive to BRD4 inhibition. Therefore, we examined distal BRD4 occupancy and uncovered a specific co-localization of BRD4 with the transcription factors C/EBPb, TEAD1, FOSL2 and JUND at putative osteoblast-specific enhancers. These findings reveal the intricacies of lineage specification and provide new insight into the context-dependent functions of BRD4.
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany.
authors.forename: Zeynab
authors.initials: Z
authors.lastname: Najafova
authors.affiliation: Institut de Biologie de l'Ecole Normale Supérieure (IBENS), CNRS, Inserm, Ecole Normale Supérieure, PSL Research University, F-75005 Paris, France.
authors.forename: Roberto
authors.initials: R
authors.lastname: Tirado-Magallanes
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Malayannan
authors.initials: M
authors.lastname: Subramaniam
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany.
authors.forename: Tareq
authors.initials: T
authors.lastname: Hossan
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany.
authors.forename: Geske
authors.initials: G
authors.lastname: Schmidt
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany.
authors.forename: Sankari
authors.initials: S
authors.lastname: Nagarajan
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Baumgart
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany.
authors.forename: Vivek Kumar
authors.initials: VK
authors.lastname: Mishra
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany.
authors.forename: Upasana
authors.initials: U
authors.lastname: Bedi
authors.affiliation: Heisenberg-Group for Molecular Skeletal Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.|Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Hesse
authors.affiliation: Institute for Pharmaceutical Chemistry, Goethe-University Frankfurt, 60323 Frankfurt am Main, Germany.|Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus, Oxford OX3 7DQ, UK.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Hawse
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany steven.johnsen@med.uni-goettingen.de.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Johnsen
mesh_terms: D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002460:Cell Line; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D051921:Fos-Related Antigen-2 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D009928:Organ Specificity; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010011:Osteocytes / Q000166:cytology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D024363:Transcription Initiation Site; D000092468:Bromodomain Containing Proteins
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051921:Fos-Related Antigen-2; D009687:Nuclear Proteins; D016755:Proto-Oncogene Proteins c-jun; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C545012:CEBPB protein, human; C497872:FOSL2 protein, human; C559371:JunD protein, human; C057182:TEAD1 protein, human