Glucocorticoid receptor and Klf4 co-regulate anti-inflammatory genes in keratinocytes

Mol Cell Endocrinol. 2015 Sep 5:412:281-9. doi: 10.1016/j.mce.2015.05.015. Epub 2015 May 19.

Abstract

The glucocorticoid (GC) receptor (GR) and Kruppel-like factor Klf4 are transcription factors that play major roles in skin homeostasis. However, whether these transcription factors cooperate in binding genomic regulatory regions in epidermal keratinocytes was not known. Here, we show that in dexamethasone-treated keratinocytes GR and Klf4 are recruited to genomic regions containing adjacent GR and KLF binding motifs to control transcription of the anti-inflammatory genes Tsc22d3 and Zfp36. GR- and Klf4 loss of function experiments showed total GR but partial Klf4 requirement for full gene induction in response to dexamethasone. In wild type keratinocytes induced to differentiate, GR and Klf4 protein expression increased concomitant with Tsc22d3 and Zfp36 up-regulation. In contrast, GR-deficient cells failed to differentiate or fully induce Klf4, Tsc22d3 and Zfp36 correlating with increased expression of the epithelium-specific Trp63, a known transcriptional repressor of Klf4. The identified transcriptional cooperation between GR and Klf4 may determine cell-type specific regulation and have implications for developing therapies for skin diseases.

Keywords: Glucocorticoid receptor; Inflammation; Keratinocyte; Kruppel-like factor 4; Transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Binding Sites
  • Cells, Cultured
  • Female
  • Gene Expression Regulation / immunology
  • Keratinocytes / immunology
  • Keratinocytes / metabolism*
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors / physiology*
  • Mice
  • Molecular Sequence Data
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Receptors, Glucocorticoid / physiology*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism

Substances

  • KLF4 protein, human
  • Klf4 protein, mouse
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors
  • Phosphoproteins
  • Protein Isoforms
  • Receptors, Glucocorticoid
  • Trans-Activators
  • Trp63 protein, mouse