Cross-enhancement of ANGPTL4 transcription by HIF1 alpha and PPAR beta/delta is the result of the conformational proximity of two response elements

Genome Biol. 2014 Apr 10;15(4):R63. doi: 10.1186/gb-2014-15-4-r63.

Abstract

Background: Synergistic transcriptional activation by different stimuli has been reported along with a diverse array of mechanisms, but the full scope of these mechanisms has yet to be elucidated.

Results: We present a detailed investigation of hypoxia-inducible factor (HIF) 1 dependent gene expression in endothelial cells which suggests the importance of crosstalk between the peroxisome proliferator-activated receptor (PPAR) β/δ and HIF signaling axes. A migration assay shows a synergistic interaction between these two stimuli, and we identify angiopoietin-like 4 (ANGPTL4) as a common target gene by using a combination of microarray and ChIP-seq analysis. We profile changes of histone marks at enhancers under hypoxia, PPARβ/δ agonist and dual stimulations and these suggest that the spatial proximity of two response elements is the principal cause of the synergistic transcription induction. A newly developed quantitative chromosome conformation capture assay shows the quantitative change of the frequency of proximity of the two response elements.

Conclusions: To the best of our knowledge, this is the first report that two different transcription factors cooperate in transcriptional regulation in a synergistic fashion through conformational change of their common target genes.

MeSH terms

  • Angiopoietin-like 4 Protein
  • Angiopoietins / genetics
  • Angiopoietins / metabolism*
  • Cell Hypoxia
  • Chromatin / chemistry
  • Chromatin / genetics
  • Chromatin Assembly and Disassembly
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • PPAR delta / genetics
  • PPAR delta / metabolism*
  • PPAR-beta / genetics
  • PPAR-beta / metabolism*
  • Response Elements*

Substances

  • ANGPTL4 protein, human
  • Angiopoietin-like 4 Protein
  • Angiopoietins
  • Chromatin
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • PPAR delta
  • PPAR-beta

Associated data

  • GEO/GSE38555
  • GEO/GSE50144
  • GEO/GSE50378