表观遗传学
KLF4公司
DNA甲基化
小RNA
癌症研究
转录因子
医学
纤维化
条件基因敲除
生物
生物信息学
表型
免疫学
基因表达
遗传学
基因
病理
SOX2
作者
Maya Malaab,Ludivine Renaud,Naoko Takamura,Kip D. Zimmerman,Willian A. da Silveira,Paula S. Ramos,Sandra Haddad,Marc Peters‐Golden,L.R.K. Penke,Bethany J. Wolf,Gary Hardiman,Carl D. Langefeld,Thomas A. Medsger,Carol Feghali‐Bostwick
标识
DOI:10.1136/annrheumdis-2021-221050
摘要
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 (KLF4, TBX5, TFAP2A and homeobox genes) and the microRNAs miR-10a and miR-10b which target several of these deregulated genes. We show that KLF4 expression is reduced in SSc dFBs and its expression is repressed by TBX5 and TFAP2A. 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.
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