Comparative Rna-seq Transcriptomic Analysis Using Ingenuity Pathway Of Unscarred Human Skin, Versus Normal Scarring And Abnormal Keloid Scars
Silvian Tan, Ping Wang, Ardeshir Bayat.
University of Manchester, Manchester, United Kingdom.
BACKGROUND Successful treatment of pathological keloid scarring is an unmet clinical challenge due to their elusive pathobiology. Keloids are fibroproliferative dermal lesions resulting from deep dermal injury and occur exclusively in humans. They exhibit quasi-neoplastic traits amongst a myriad of other characteristics although it is not clear how they are related. Based on the central dogma of biology, we hypothesize that a comprehensive exploration of the keloid scar transcriptome can reveal novel biological patterns to explain its pathobiology in relation to normal scarring and skin. Current studies on the keloid transcriptome are based on PCR and microarray studies, which are limited in their dynamic range. METHODS To approach our hypothesis, we performed comparative transcriptomic analysis of the human skin, normal scar and keloid tissues using RNA-seq. This was conducted using Illumina HiSeq 4000 for 8 skin (C), 4 scar (S) and 11 keloid (K) samples obtained from 20 patients, resulting in pairwise comparison across 3 groups: keloid versus skin (KC), scar versus skin (SC) and keloid versus scar (KS). RESULTS We identified 7120, 2748 and 150 differentially expressed genes (p-adj<0.05) in KC, SC and KS respectively using DESeq2. Further exploration of these genes using Gene Ontology and Ingenuity Pathway Analysis revealed unprecedented gene signatures alongside biological processes and pathways, which may contribute to the unique phenotype of the disease. We confirmed the presence of dysregulated extracellular matrix metabolism, which is underlined by processes relating to increased cell survivability. In particular, we highlighted the putative role of a dysregulated mechanism in keloids encompassing transcription, translation and post-translational modifications of proteins. CONCLUSIONS This is the first comprehensive study of the keloid transcriptome using RNA-seq. It confirms our hypothesis and sheds new insights into keloid pathobiology, supporting the identification of candidate biomarkers and pathways for further study geared towards better therapeutic development.
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