A novel Nrf2-miR-29-desmocollin-2 axis regulates desmosome function in keratinocytes

Svitlana Kurinna, Matthias Schäfer, Paola Ostano, Emmanuel Karouzakis, Giovanna Chiorino, Wilhelm Bloch, Andreas Bachmann, Steffen Gay, David Garrod, Karine Lefort, Gian-Paolo Dotto, Hans-Dietmar Beer, Sabine Werner

Research output: Contribution to journalArticlepeer-review

Abstract

The Nrf2 transcription factor controls the expression of genes involved in the antioxidant defense system. Here, we identified Nrf2 as a novel regulator of desmosomes in the epidermis through the regulation of microRNAs. On Nrf2 activation, expression of miR-29a and miR-29b increases in cultured human keratinocytes and in mouse epidermis. Chromatin immunoprecipitation identified the Mir29ab1 and Mir29b2c genes as direct Nrf2 targets in keratinocytes. While binding of Nrf2 to the Mir29ab1 gene activates expression of miR-29a and -b, the Mir29b2c gene is silenced by DNA methylation. We identified desmocollin-2 (Dsc2) as a major target of Nrf2-induced miR-29s. This is functionally important, since Nrf2 activation in keratinocytes of transgenic mice causes structural alterations of epidermal desmosomes. Furthermore, the overexpression of miR-29a/b or knockdown of Dsc2 impairs the formation of hyper-adhesive desmosomes in keratinocytes, whereas Dsc2 overexpression has the opposite effect. These results demonstrate that a novel Nrf2-miR-29-Dsc2 axis controls desmosome function and cutaneous homeostasis.

Original languageEnglish
Article number5099
JournalNature Communications
Volume5
DOIs
Publication statusPublished - 6 Oct 2014

Keywords

  • Animals
  • Base Sequence
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • CpG Islands
  • DNA Methylation
  • Desmocollins/metabolism
  • Desmosomes/metabolism
  • Gene Expression Regulation
  • Gene Silencing
  • Homeostasis
  • Humans
  • Keratinocytes/cytology
  • Membrane Glycoproteins/metabolism
  • Mice
  • Mice, Transgenic
  • MicroRNAs/metabolism
  • Molecular Sequence Data
  • NF-E2-Related Factor 2/metabolism
  • Skin/metabolism

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