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Nucleic Acids Res. 2017 Jan 9;45(1):127-141. doi: 10.1093/nar/gkw826. Epub 2016 Sep 19.

BRD4 localization to lineage-specific enhancers is associated with a distinct transcription factor repertoire.

Author information

1
Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany.
2
Institut de Biologie de l'Ecole Normale Supérieure (IBENS), CNRS, Inserm, Ecole Normale Supérieure, PSL Research University, F-75005 Paris, France.
3
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
4
Heisenberg-Group for Molecular Skeletal Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
5
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
6
Institute for Pharmaceutical Chemistry, Goethe-University Frankfurt, 60323 Frankfurt am Main, Germany.
7
Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus, Oxford OX3 7DQ, UK.
8
Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany steven.johnsen@med.uni-goettingen.de.

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.

PMID:
27651452
PMCID:
PMC5224504
DOI:
10.1093/nar/gkw826
[Indexed for MEDLINE]
Free PMC Article

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