Antifibrotic factor KLF4 is repressed by the miR-10/TFAP2A/TBX5 axis in dermal fibroblasts: insights from twins discordant for systemic sclerosis.
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 path...
| Publicado en: | Annals of the Rheumatic Diseases Vol. 81; no. 2; pp. 268 - 278 |
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| Autores principales: | , , , , , , , , , , , , , |
| Formato: | research Journal Article |
| Publicado: |
Elsevier B.V.
Feb2022
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=154805342&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 154805342 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00034967 ANR jtl: Annals of the Rheumatic Diseases issn: 00034967 maglogo: N pubinfo: dt: Feb2022 vid: 81 iid: 2 pid: 467 pub: Elsevier B.V. place: New York, New York artinfo: ui: 154805342 154805342 NLM34750102 154805342 10.1136/annrheumdis-2021-221050 NLM34750102 154805342 ppf: 268 ppct: 10 formats: tig: atl: Antifibrotic factor KLF4 is repressed by the miR-10/TFAP2A/TBX5 axis in dermal fibroblasts: insights from twins discordant for systemic sclerosis. aug: au: Malaab, Maya Renaud, Ludivine Takamura, Naoko Zimmerman, Kip D. da Silveira, Willian A. Ramos, Paula S. Haddad, Sandra Peters-Golden, Marc Penke, Loka R. Wolf, Bethany Hardiman, Gary Langefeld, Carl D. Medsger, Thomas A. Feghali-Bostwick, Carol A. affil: Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA. sug: 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. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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