Identification and characterization of BATF3 as a context-specific coactivator of the glucocorticoid receptor

PLoS One. 2017 Jul 14;12(7):e0181219. doi: 10.1371/journal.pone.0181219. eCollection 2017.

Abstract

The ability of the glucocorticoid receptor (GR) to regulate the transcriptional output of genes relies on its interactions with transcriptional coregulators. However, which coregulators are required for GR-dependent activation is context-dependent and can be influenced by the sequence of the DNA bound by GR and by the nature of the GR isoform responsible for the regulation of a gene. Here, we screened for GR-interacting proteins for which the interaction signal differed between two GR isoforms GRα and GRγ. These isoforms diverge by a single amino acid insertion in a domain, the lever arm, which adopts DNA sequence-specific conformations. We identify Basic Leucine Zipper ATF-Like Transcription Factor 3 (BATF3), an AP-1 family transcription factor, as a GR coregulator whose interaction with GR is modulated by the lever arm. Further, a combination of experiments uncovered that BATF3 acts as a gene-specific coactivator of GR whose coactivator potency is influenced by the sequence of the GR binding site. Together, our findings suggest that GR isoform and the sequence of GR binding site influence the interaction of GR with BATF3, which might direct the assembly of gene-specific regulatory complexes to fine-tune the expression of individual GR target genes.

MeSH terms

  • Basic-Leucine Zipper Transcription Factors / antagonists & inhibitors
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • Cell Line, Tumor
  • Genes, Reporter
  • Humans
  • Immunoprecipitation
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Receptors, Glucocorticoid / antagonists & inhibitors
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism*
  • Repressor Proteins / antagonists & inhibitors
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Transcriptional Activation
  • Two-Hybrid System Techniques

Substances

  • BATF3 protein, human
  • Basic-Leucine Zipper Transcription Factors
  • JDP2 protein, human
  • Protein Isoforms
  • RNA, Small Interfering
  • Receptors, Glucocorticoid
  • Repressor Proteins

Grant support

This work was supported by the Max Planck Society and the Deutsche Forschungsgemeinschaft (DFG, grant number: ME4154/1-1) (http://www.dfg.de). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.