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A Methylome and Transcriptome Analysis of Normal Human Scar Cells Reveals a Role for FOXF2 in Scar Maintenance

  • Andrew W. Stevenson
    Correspondence
    Correspondence: Andrew W. Stevenson, Burn Injury Research Unit, Room 509, UWA FHMS Level 5, Harry Perkins Institute of Medical Research, QQ Block, 6 Verdun St, Nedlands, WA, 6009, Australia.
    Affiliations
    Burn Injury Research Unit, School of Biomedical Sciences, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, Australia
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  • Phillip E. Melton
    Affiliations
    School of Population and Global Health, The University of Western Australia, Perth, Australia

    School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Perth, Australia

    Menzies Research Institute, University of Tasmania, Hobart, Tasmania, Australia
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  • Eric.K. Moses
    Affiliations
    School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Perth, Australia

    Menzies Research Institute, University of Tasmania, Hobart, Tasmania, Australia

    School of Biomedical Sciences, University of Western Australia, Crawley, Western Australia, Australia
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  • Hilary J. Wallace
    Affiliations
    Burn Injury Research Unit, School of Biomedical Sciences, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, Australia

    School of Medicine, The University of Notre Dame Australia, Fremantle, Australia
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  • Fiona M. Wood
    Affiliations
    Burn Injury Research Unit, School of Biomedical Sciences, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, Australia

    Burns Service of Western Australia, Perth Children’s Hospital and Fiona Stanley Hospital, Perth, Australia
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  • Suzanne Rea
    Affiliations
    Burns Service of Western Australia, Perth Children’s Hospital and Fiona Stanley Hospital, Perth, Australia
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  • Patricia L. Danielsen
    Affiliations
    Department of Dermatology and Copenhagen Wound Healing Center, Copenhagen University Hospital, Copenhagen, Denmark
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  • Mansour Alghamdi
    Affiliations
    Department of Anatomy, College of Medicine, King Khalid University, Abha, Saudi Arabia

    Genomics and Personalised Medicine Unit, College of Medicine, King Khalid University, Abha, Saudi Arabia
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  • Nicole Hortin
    Affiliations
    Burn Injury Research Unit, School of Biomedical Sciences, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, Australia
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  • Julia Borowczyk
    Affiliations
    Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
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  • Zhenjun Deng
    Affiliations
    Burn Injury Research Unit, School of Biomedical Sciences, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, Australia
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  • Mitali Manzur
    Affiliations
    Telethon Kids Institute, Northern Entrance, Perth Children’s Hospital, Nedlands, Australia
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  • Mark W. Fear
    Affiliations
    Burn Injury Research Unit, School of Biomedical Sciences, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, Australia
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Published:October 20, 2021DOI:https://doi.org/10.1016/j.jid.2021.08.445
      Scars are maintained for life and increase in size during periods of growth such as puberty. Epigenetic changes in fibroblasts after injury may underpin the maintenance and growth of scars. In this study, we combined methylome and transcriptome data from normotrophic mature scar and contralateral uninjured normal skin fibroblasts to identify potential regulators of scar maintenance. In total, 219 significantly differentially expressed and 1,199 significantly differentially methylated promoters were identified, of which there were 12 genes both significantly differentially methylated and expressed. Of these, the two transcription factors, FOXF2 and MKX, were selected for further analysis. Immunocytochemistry and qPCR suggested that FOXF2 but not MKX had elevated expression in scar fibroblasts. Using RNA sequencing, FOXF2 knockdown was shown to significantly reduce the expression of extracellular matrix‒related genes, whereas MKX did not appear to affect similar pathways. Finally, FOXF2 knockdown was also shown to significantly decrease collagen I production in scar and keloid fibroblasts. This study provides insights into the maintenance of normotrophic scar, suggesting that FOXF2 is an important regulator of this process. Targeting genes responsible for maintenance of scar phenotype may ameliorate scar appearance and improve patient outcomes in the future.

      Graphical abstract

      Abbreviations:

      ECM (extracellular matrix), GO (Gene Ontology), RNA-seq (RNA sequencing), siRNA (small interfering RNA)
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