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.

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
  • 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
  • TEAD1 protein, human
  • Transcription Factors