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

Mélanie Salamito1, Benjamin Gillet2, Delfien Syx3

  • 1Université 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.

The Journal of Investigative Dermatology
|March 15, 2024
PubMed

Insights

Nuclear factor erythroid 2-related factor 2 (NRF2) regulates extracellular matrix (ECM) gene expression in skin fibroblasts. Downregulating NRF2 reduces collagen I production and impacts ECM deposition, crucial for skin homeostasis.

Area of Science:

  • Dermatology
  • Molecular Biology
  • Cell Biology

Background:

  • Nuclear factor erythroid 2-related factor 2 (NRF2) is a key regulator of cellular antioxidant responses.
  • NRF2's role in regulating extracellular matrix (ECM) gene expression, particularly in skin fibroblasts, is an emerging area of research.
  • Understanding NRF2's function in dermal fibroblasts is vital for maintaining skin homeostasis and developing anti-aging strategies.

Purpose of the Study:

  • To investigate the impact of NRF2 downregulation on the expression of matrisome genes in human primary dermal fibroblasts.
  • To analyze the effects of NRF2 on ECM deposition and collagen biosynthesis in skin cells.
  • To identify potential downstream targets of NRF2 involved in ECM regulation.

Main Methods:

  • RNA-sequencing was employed to analyze the transcriptome of NRF2-silenced dermal fibroblasts.
  • Light and electron microscopy were used to assess ECM deposits and collagen fibril structure.
  • Gene silencing of ZNF469 and analysis of fibroblasts from patients with ZNF469 variants were performed.

Main Results:

  • Transcriptome analysis revealed that ECM genes were the most significantly regulated gene sets upon NRF2 downregulation.
  • NRF2 deprivation led to reduced collagen I biosynthesis and altered collagen fibril deposition in dermal fibroblasts.
  • ZNF469 was identified as a direct or indirect NRF2 target, and its downregulation or mutation decreased collagen I gene expression.

Conclusions:

  • NRF2 plays a critical role in orchestrating matrisome expression in human skin fibroblasts.
  • NRF2 influences dermal ECM homeostasis through transcriptional regulation of ECM genes, including ZNF469.
  • Targeting the NRF2-mediated matrisome pathway holds potential for addressing dermal ECM imbalances in health and disease.

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