title: A novel Nrf2-miR-29-desmocollin-2 axis regulates desmosome function in keratinocytes.
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.
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland.
authors.forename: Svitlana
authors.initials: S
authors.lastname: Kurinna
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schäfer
authors.affiliation: Laboratory of Cancer Genomics, Fondazione Edo ed Elvo Tempia, 13900 Biella, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Ostano
authors.affiliation: Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Karouzakis
authors.affiliation: Laboratory of Cancer Genomics, Fondazione Edo ed Elvo Tempia, 13900 Biella, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Chiorino
authors.affiliation: Department of Molecular and Cellular Sport Medicine, German Sport University Cologne, 50933 Cologne, Germany.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Bloch
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bachmann
authors.affiliation: Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Steffen
authors.initials: S
authors.lastname: Gay
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: David
authors.initials: D
authors.lastname: Garrod
authors.affiliation: Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
authors.forename: Karine
authors.initials: K
authors.lastname: Lefort
authors.affiliation: Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
authors.forename: Gian-Paolo
authors.initials: GP
authors.lastname: Dotto
authors.affiliation: Department of Dermatology, University Hospital Zurich, 8006 Zurich, Switzerland.
authors.forename: Hans-Dietmar
authors.initials: HD
authors.lastname: Beer
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Werner
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D018899:CpG Islands; D019175:DNA Methylation; D051187:Desmocollins / Q000378:metabolism*; D003896:Desmosomes / Q000378:metabolism*; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006706:Homeostasis; D006801:Humans; D015603:Keratinocytes / Q000166:cytology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D008969:Molecular Sequence Data; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D012867:Skin / Q000378:metabolism
chemical_list: C081561:DSC2 protein, human; D051187:Desmocollins; C489912:Dsc2 protein, mouse; C547014:MIRN29 microRNA, mouse; C532045:MIRN29a microRNA, human; D008562:Membrane Glycoproteins; D035683:MicroRNAs; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse