title: Glucocorticoid receptor and Klf4 co-regulate anti-inflammatory genes in keratinocytes.
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.
authors.affiliation: Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas (IBV-CSIC), Jaime Roig 11, E-46010 Valencia, Spain.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Sevilla
authors.affiliation: Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas (IBV-CSIC), Jaime Roig 11, E-46010 Valencia, Spain; Faculty of Human and Medical Sciences, The University of Manchester, Manchester, UK.
authors.forename: Víctor
authors.initials: V
authors.lastname: Latorre
authors.affiliation: Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas (IBV-CSIC), Jaime Roig 11, E-46010 Valencia, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Carceller
authors.affiliation: Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas (IBV-CSIC), Jaime Roig 11, E-46010 Valencia, Spain.
authors.forename: Julia
authors.initials: J
authors.lastname: Boix
authors.affiliation: Bioinformatics Core Facility, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Norway.
authors.forename: Daniel
authors.initials: D
authors.lastname: Vodák
authors.affiliation: Prostate Cancer Research Group, Centre for Molecular Medicine (Norway), University of Oslo and Oslo University Hospitals, Oslo, Norway; Department of Molecular Oncology, Oslo University Hospitals, Oslo, Norway; Department of Urology, Oslo University Hospitals, Oslo, Norway; FASTMAN Movember Centre of Excellence, CCRCB, Queens University, Belfast, UK.
authors.forename: Ian Geoffrey
authors.initials: IG
authors.lastname: Mills
authors.affiliation: Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas (IBV-CSIC), Jaime Roig 11, E-46010 Valencia, Spain. Electronic address: pperez@ibv.csic.es.
authors.forename: Paloma
authors.initials: P
authors.lastname: Pérez
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D015603:Keratinocytes / Q000276:immunology / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D010750:Phosphoproteins; D020033:Protein Isoforms; D011965:Receptors, Glucocorticoid; D015534:Trans-Activators; C486419:Trp63 protein, mouse
keywords: Glucocorticoid receptor; Inflammation; Keratinocyte; Kruppel-like factor 4; Transcription