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Abstract

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.

Item Type:	Article
Authors/Creators:	Stevenson, AW and Melton, PE and Moses, EK and Wallace, HJ and Wood, FM and Rea, S and Danielsen, PL and Alghamdi, M and Hortin, N and Borowczyk, J and Deng, Z and Manzur, M and Fear, MW
Keywords:	scars, wound healing, DNA methylation, RNA-Seq, FOXF2, MKX
Journal or Publication Title:	The Journal of Investigative Dermatology
Publisher:	Blackwell Publishing Inc
ISSN:	0022-202X
DOI / ID Number:	https://doi.org/10.1016/j.jid.2021.08.445
Copyright Information:	Copyright 2021 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology
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