RT Journal Article
SR Electronic
T1 Antifibrotic factor KLF4 is repressed by the miR-10/TFAP2A/TBX5 axis in dermal fibroblasts: insights from twins discordant for systemic sclerosis
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP 268
OP 277
DO 10.1136/annrheumdis-2021-221050
VO 81
IS 2
A1 Maya Malaab
A1 Ludivine Renaud
A1 Naoko Takamura
A1 Kip D Zimmerman
A1 Willian A da Silveira
A1 Paula S Ramos
A1 Sandra Haddad
A1 Marc Peters-Golden
A1 Loka R Penke
A1 Bethany Wolf
A1 Gary Hardiman
A1 Carl D Langefeld
A1 Thomas A Medsger
A1 Carol A Feghali-Bostwick
YR 2022
UL http://ard.bmj.com/content/81/2/268.abstract
AB Objectives 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.Methods 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.Results 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.Conclusions 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.Data are available in a public, open access repository. Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. The data supporting the findings of this study are available within the paper and its supplementary information files. Normalized or raw intensity data of the HM450K BeadChips are available upon request from the authors on a collaborative basis. RNAseq data have been deposited on the NCBI GEO under access # GSE153880.