NRF2 Shortage in Human Skin Fibroblasts Dysregulates Matrisome Gene Expression and Affects Collagen Fibrillogenesis.

Autor:	Salamito M; Université de Lyon, École Normal Supérieure de Lyon (ENSL), Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle de Lyon (IGFL), Université Claude Bernard Lyon 1, Lyon, France; L'Oréal Research & Innovation, Aulnay-sous-Bois, France., Gillet B; Université de Lyon, École Normal Supérieure de Lyon (ENSL), Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle de Lyon (IGFL), Université Claude Bernard Lyon 1, Lyon, France., Syx D; Center for Medical Genetics Ghent, Department of Biomolecular Medicine, Ghent University Hospital, Ghent University, Ghent, Belgium; Ghent University Hospital, Ghent University, Ghent, Belgium., Vaganay E; Université de Lyon, École Normal Supérieure de Lyon (ENSL), Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle de Lyon (IGFL), Université Claude Bernard Lyon 1, Lyon, France., Malbouyres M; Université de Lyon, École Normal Supérieure de Lyon (ENSL), Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle de Lyon (IGFL), Université Claude Bernard Lyon 1, Lyon, France., Cerutti C; Université de Lyon, École Normal Supérieure de Lyon (ENSL), Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle de Lyon (IGFL), Université Claude Bernard Lyon 1, Lyon, France., Tissot N; L'Oréal Research & Innovation, Aulnay-sous-Bois, France., Exbrayat-Héritier C; Université de Lyon, École Normal Supérieure de Lyon (ENSL), Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle de Lyon (IGFL), Université Claude Bernard Lyon 1, Lyon, France., Perez P; L'Oréal Research & Innovation, Aulnay-sous-Bois, France., Jones C; L'Oréal Research & Innovation, Aulnay-sous-Bois, France., Hughes S; Université de Lyon, École Normal Supérieure de Lyon (ENSL), Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle de Lyon (IGFL), Université Claude Bernard Lyon 1, Lyon, France., Malfait F; Center for Medical Genetics Ghent, Department of Biomolecular Medicine, Ghent University Hospital, Ghent University, Ghent, Belgium; Ghent University Hospital, Ghent University, Ghent, Belgium., Haydont V; L'Oréal Research & Innovation, Aulnay-sous-Bois, France., Jäger S; L'Oréal Research & Innovation, Aulnay-sous-Bois, France., Ruggiero F; Université de Lyon, École Normal Supérieure de Lyon (ENSL), Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle de Lyon (IGFL), Université Claude Bernard Lyon 1, Lyon, France. Electronic address: florence.ruggiero@ens-lyon.fr.
Jazyk:	angličtina
Zdroj:	The Journal of investigative dermatology [J Invest Dermatol] 2023 Mar; Vol. 143 (3), pp. 386-397.e12. Date of Electronic Publication: 2022 Sep 20.
DOI:	10.1016/j.jid.2022.07.034
Abstrakt:	NRF2 is a master regulator of the antioxidative response that was recently proposed as a potential regulator of extracellular matrix (ECM) gene expression. Fibroblasts are major ECM producers in all connective tissues, including the dermis. A better understanding of NRF2-mediated ECM regulation in skin fibroblasts is thus of great interest for skin homeostasis maintenance and aging protection. In this study, we investigate the impact of NRF2 downregulation on matrisome gene expression and ECM deposits in human primary dermal fibroblasts. RNA-sequencing‒based transcriptome analysis of NRF2 silenced dermal fibroblasts shows that ECM genes are the most regulated gene sets, highlighting the relevance of the NRF2-mediated matrisome program in these cells. Using complementary light and electron microscopy methods, we show that NRF2 deprivation in dermal fibroblasts results in reduced collagen I biosynthesis and impacts collagen fibril deposition. Moreover, we identify ZNF469, a putative transcriptional regulator of collagen biosynthesis, as a target of NRF2. Both ZNF469 silenced fibroblasts and fibroblasts derived from Brittle Corneal Syndrome patients carrying variants in ZNF469 gene show reduced collagen I gene expression. Our study shows that NRF2 orchestrates matrisome expression in human skin fibroblasts through direct or indirect transcriptional mechanisms that could be prioritized to target dermal ECM homeostasis in health and disease. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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