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

Zeynab Najafova; Roberto Tirado-Magallanes; Malayannan Subramaniam; Tareq Hossan; Geske Schmidt; Sankari Nagarajan; Simon J Baumgart; Vivek Kumar Mishra; Upasana Bedi; Eric Hesse; Stefan Knapp; John R Hawse; Steven A Johnsen

doi:10.1093/nar/gkw826

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

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

Authors

Affiliations

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 [email protected].

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.

MeSH terms

CCAAT-Enhancer-Binding Protein-beta / genetics
CCAAT-Enhancer-Binding Protein-beta / metabolism
Cell Cycle Proteins
Cell Differentiation
Cell Line
Cell Line, Tumor
Cell Lineage / genetics*
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Epigenesis, Genetic*
Epithelial Cells / cytology
Epithelial Cells / metabolism*
Fos-Related Antigen-2 / genetics
Fos-Related Antigen-2 / metabolism
Gene Expression Profiling
Humans
Mesenchymal Stem Cells / cytology
Mesenchymal Stem Cells / metabolism*
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
Organ Specificity
Osteoblasts / cytology
Osteoblasts / metabolism*
Osteocytes / cytology
Osteocytes / metabolism*
Promoter Regions, Genetic
Protein Binding
Proto-Oncogene Proteins c-jun / genetics
Proto-Oncogene Proteins c-jun / metabolism
Signal Transduction
TEA Domain Transcription Factors
Transcription Factors / genetics*
Transcription Factors / metabolism
Transcription Initiation Site

Substances

BRD4 protein, human
CCAAT-Enhancer-Binding Protein-beta
CEBPB protein, human
Cell Cycle Proteins
DNA-Binding Proteins
FOSL2 protein, human
Fos-Related Antigen-2
JunD protein, human
Nuclear Proteins
Proto-Oncogene Proteins c-jun
TEA Domain Transcription Factors
TEAD1 protein, human
Transcription Factors

Grants and funding

R01 DE014036/DE/NIDCR NIH HHS/United States