title: Similarities and differences in the transcriptional control of expression of the mouse TSLP gene in skin epidermis and intestinal epithelium.
abstract: We previously reported that selective ablation of the nuclear receptors retinoid X receptor (RXR)-α and RXR-β in mouse epidermal keratinocytes (RXR-αβep-/-) or a topical application of active vitamin D3 (VD3) and/or all-trans retinoic acid (RA) on wild-type mouse skin induces a human atopic dermatitis-like phenotype that is triggered by an increased expression of the thymic stromal lymphopoietin (TSLP) proinflammatory cytokine. We demonstrate here that in epidermal keratinocytes, unliganded heterodimers of vitamin D receptor (VDR)/RXR-α and retinoic acid receptor-γ (RAR-γ)/RXR-β are bound as repressing complexes to their cognate DNA-binding sequence(s) (DBS) in the TSLP promoter regulatory region. Treatments with either an agonistic VD3 analog or RA dissociate the repressing complexes and recruit coactivator complexes and RNA polymerase II, thereby inducing transcription. Furthermore, we identified several functional NF-κB, activator protein 1 (AP1), STAT, and Smad DBS in the TSLP promoter region. Interestingly, many of these transcription factors and DBS present in the TSLP promoter region are differentially used in intestinal epithelial cell(s) (IEC). Collectively, our study reveals that, in vivo within their heterodimers, the RXR and RAR isotypes are not functionally redundant, and it also unveils the combinatorial mechanisms involved in the tissue-selective regulation of TSLP transcription in epidermal keratinocytes and IEC.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS UMR7104, INSERM U964), Illkirch 67404, France.|University of Strasbourg Institute for Advanced Study, F-67083 Strasbourg, France.|Collège de France, 75005 Paris, France.
authors.forename: Krishna Priya
authors.initials: KP
authors.lastname: Ganti
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS UMR7104, INSERM U964), Illkirch 67404, France.|University of Strasbourg Institute for Advanced Study, F-67083 Strasbourg, France.|Collège de France, 75005 Paris, France.
authors.forename: Atish
authors.initials: A
authors.lastname: Mukherji
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS UMR7104, INSERM U964), Illkirch 67404, France.|University of Strasbourg Institute for Advanced Study, F-67083 Strasbourg, France.|Collège de France, 75005 Paris, France.|Translational Health Science and Technology Institute, National Capital Region Biotech Science Cluster, Faridabad-121001, India.
authors.forename: Milan
authors.initials: M
authors.lastname: Surjit
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS UMR7104, INSERM U964), Illkirch 67404, France.|University of Strasbourg Institute for Advanced Study, F-67083 Strasbourg, France.
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS UMR7104, INSERM U964), Illkirch 67404, France; chambon@igbmc.fr.|University of Strasbourg Institute for Advanced Study, F-67083 Strasbourg, France.|Collège de France, 75005 Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D004817:Epidermis / Q000378:metabolism*; D005786:Gene Expression Regulation; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D055503:Protein Multimerization; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D047488:Retinoid X Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D000094632:Thymic Stromal Lymphopoietin; D000097768:Retinoic Acid Receptor gamma
chemical_list: D016207:Cytokines; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D000094632:Thymic Stromal Lymphopoietin; D000097768:Retinoic Acid Receptor gamma; C000721967:TSLP protein, mouse
keywords: NF-κB; TSLP transcription; intestine; nuclear receptors; skin