Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
Biostatistical Sciences and Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
Ann Rheum Dis. 2022 Feb;81(2):268-277. doi: 10.1136/annrheumdis-2021-221050. Epub 2021 Nov 8.
Systemic sclerosis (SSc) is a complex disease of unknown aetiology in which inflammation and fibrosis lead to multiple organ damage. There is currently no effective therapy that can halt the progression of fibrosis or reverse it, thus studies that provide novel insights into disease pathogenesis and identify novel potential therapeutic targets are critically needed.
We used global gene expression and genome-wide DNA methylation analyses of dermal fibroblasts (dFBs) from a unique cohort of twins discordant for SSc to identify molecular features of this pathology. We validated the findings using in vitro, ex vivo and in vivo models.
Our results revealed distinct differentially expressed and methylated genes, including several transcription factors involved in stem cell differentiation and developmental programmes (, , and genes) and the microRNAs and which target several of these deregulated genes. We show that expression is reduced in SSc dFBs and its expression is repressed by and . We also show that KLF4 is antifibrotic, and its conditional knockout in fibroblasts promotes a fibrotic phenotype.
Our data support a role for epigenetic dysregulation in mediating SSc susceptibility in dFBs, illustrating the intricate interplay between CpG methylation, miRNAs and transcription factors in SSc pathogenesis, and highlighting the potential for future use of epigenetic modifiers as therapies.
系统性硬化症（SSc）是一种病因不明的复杂疾病，其炎症和纤维化导致多器官损伤。目前尚无有效的治疗方法可以阻止纤维化的进展或使其逆转，因此，迫切需要研究为疾病发病机制提供新的见解，并确定新的潜在治疗靶点。
我们使用来自一组独特的双胞胎的皮肤成纤维细胞（dFB）的全基因组基因表达和全基因组 DNA 甲基化分析，来鉴定这种病理学的分子特征。我们使用体外、离体和体内模型验证了这些发现。
我们的结果揭示了明显差异表达和甲基化的基因，包括几个参与干细胞分化和发育程序的转录因子（、、和基因）以及靶向这些失调基因的 microRNAs 和 。我们表明，在 SSc dFBs 中表达减少，并且其表达受 和 抑制。我们还表明 KLF4 具有抗纤维化作用，其在成纤维细胞中的条件性敲除可促进纤维化表型。
我们的数据支持表观遗传失调在介导 dFBs 中 SSc 易感性中的作用，说明了 CpG 甲基化、miRNAs 和转录因子在 SSc 发病机制中的复杂相互作用，并突出了未来使用表观遗传修饰剂作为治疗方法的潜力。
