Journal Article

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

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

2022

Overview

ObjectivesSystemic 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.MethodsWe 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.ResultsOur 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.ConclusionsOur 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.

• Publisher: BMJ Publishing Group Ltd and European League Against Rheumatism,Elsevier Limited
• Subject: AP-2 protein / Cell differentiation / Cells, Cultured / Connective tissue diseases / CpG islands / DNA methylation / Epigenetics / Etiology / Fibroblasts / Fibroblasts - metabolism / Fibroblasts - pathology / Fibrosis / Gene expression / Gene Expression Regulation - physiology / Genomes / Homeobox / Humans / KLF4 protein / Kruppel-Like Factor 4 - genetics / Kruppel-Like Factor 4 - metabolism / MicroRNAs / MicroRNAs - metabolism / miRNA / Morphogenesis / Mutation / Ontology / Pathogenesis / Phenotypes / Scleroderma / Scleroderma, Systemic - genetics / Scleroderma, Systemic - metabolism / Scleroderma, Systemic - pathology / Skin - metabolism / Skin - pathology / Stem cells / systemic / Systemic sclerosis / T-Box Domain Proteins - metabolism / Therapeutic targets / Transcription Factor AP-2 - metabolism / Transcription factors / Transcriptome / Twins