Antifibrotic factor KLF4 is repressed by the miR-10/TFAP2A/TBX5 axis in dermal fibroblasts: insights from twins discordant for systemic sclerosis

Maya Malaab, Ludivine Renaud, Naoko Takamura, Kip D Zimmerman, Willian A da Silveira, Paula S Ramos, Sandra Haddad, Marc Peters-Golden, Loka R Penke, Bethany Wolf, Gary Hardiman, Carl D Langefeld, Thomas A Medsger, Carol A Feghali-Bostwick

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
JournalAnnals of the rheumatic diseases
Early online date08 Nov 2021
DOIs
Publication statusEarly online date - 08 Nov 2021

Keywords

  • scleroderma
  • fibroblasts
  • systemic sclerosis
  • systemic

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