Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai Key Laboratory of Tissue Engineering Research, Shanghai, China.
PLoS Genet. 2022 Jun 16;18(6):e1010168. doi: 10.1371/journal.pgen.1010168. eCollection 2022 Jun.
Keloid disorder is a tumour-like disease with invasive growth and a high recurrence rate. Genetic contribution is well expected due to the presence of autosomal dominant inheritance and various genetic mutations in keloid lesions. However, GWAS failed to reveal functional variants in exon regions but single nucleotide polymorphisms in the non-coding regions, suggesting the necessity of innovative genetic investigation. This study employed combined GWAS, RNA-sequence and Hi-C analyses to dissect keloid disorder genetic mechanisms using paired keloid tissues and normal skins. Differentially expressed genes, miRNAs and lncRNAs mined by RNA-sequence were identified to construct a network. From which, 8 significant pathways involved in keloid disorder pathogenesis were enriched and 6 of them were verified. Furthermore, topologically associated domains at susceptible loci were located via the Hi-C database and ten differentially expressed RNAs were identified. Among them, the functions of six molecules for cell proliferation, cell cycle and apoptosis were particularly examined and confirmed by overexpressing and knocking-down assays. This study firstly revealed unknown key biomarkers and pathways in keloid lesions using RNA-sequence and previously reported mutation loci, indicating a feasible approach to reveal the genetic contribution to keloid disorder and possibly to other diseases that are failed by GWAS analysis alone.
瘢痕疙瘩病是一种具有侵袭性生长和高复发率的肿瘤样疾病。由于常染色体显性遗传和瘢痕疙瘩病变中的各种基因突变的存在，遗传贡献是可以预期的。然而，GWAS 未能揭示外显子区域的功能变异，而仅揭示了非编码区域的单核苷酸多态性，这表明需要进行创新性的遗传研究。本研究采用联合 GWAS、RNA-seq 和 Hi-C 分析，使用配对的瘢痕疙瘩组织和正常皮肤来剖析瘢痕疙瘩病的遗传机制。通过 RNA-seq 鉴定出差异表达的基因、miRNAs 和 lncRNAs，构建了一个网络。其中，有 8 个显著的通路参与了瘢痕疙瘩病的发病机制，并对其中的 6 个通路进行了验证。此外，通过 Hi-C 数据库定位了易感位点的拓扑相关结构域，并鉴定了 10 个差异表达的 RNA。其中，对 6 种与细胞增殖、细胞周期和细胞凋亡相关的分子的功能进行了特别的研究和验证。本研究首次通过 RNA-seq 和之前报道的突变位点揭示了瘢痕疙瘩病变中未知的关键生物标志物和通路，表明这是一种可行的方法，可以揭示瘢痕疙瘩病和其他可能因 GWAS 分析失败的疾病的遗传贡献。
