A methylome and transcriptome analysis of normal human scar cells reveals a role for FOXF2 in scar maintenance.

Scar is maintained for life and increases in size during periods of growth such as puberty. Epigenetic changes in fibroblasts after injury may underpin the maintenance and growth of scar. Here, we, combined methylome and transcriptome data from normotrophic mature scar and contralateral uninjured normal skin fibroblasts to identify potential regulators of scar maintenance. 219 significantly differentially expressed and 1199 significantly differentially methylated promoters were identified, of which there were 12 genes both significantly differentially methylated and expressed. Of these the two transcription factors, Forkhead Box F2 (FOXF2) and Mohawk Homeobox (MKX) were selected for further analysis. Immunocytochemistry and qPCR suggested FOXF2 but not MKX had elevated expression in scar fibroblasts. Using RNASeq, FOXF2 knockdown was shown to significantly reduce expression of extracellular matrix related genes, whilst 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 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.