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Malaab M, Renaud L, Takamura N, et al. Antifibrotic factor KLF4 is repressed by the miR-10/TFAP2A/TBX5 axis in dermal fibroblasts: insights from twins discordant for systemic sclerosis. Ann Rheum Dis. 2021;doi: 10.1136/annrheumdis-2021-221050.
Malaab, M., Renaud, L., Takamura, N., Zimmerman, K. D., da Silveira, W. A., Ramos, P. S., Haddad, S., Peters-Golden, M., Penke, L. R., Wolf, B., Hardiman, G., Langefeld, C. D., Medsger, T. A., & Feghali-Bostwick, C. A. (2021). Antifibrotic factor KLF4 is repressed by the miR-10/TFAP2A/TBX5 axis in dermal fibroblasts: insights from twins discordant for systemic sclerosis. Annals of the rheumatic diseases, . https://doi.org/10.1136/annrheumdis-2021-221050
Malaab, Maya, et al. "Antifibrotic factor KLF4 is repressed by the miR-10/TFAP2A/TBX5 axis in dermal fibroblasts: insights from twins discordant for systemic sclerosis." Annals of the rheumatic diseases vol. (2021). doi: https://doi.org/10.1136/annrheumdis-2021-221050
Malaab M, Renaud L, Takamura N, Zimmerman KD, da Silveira WA, Ramos PS, Haddad S, Peters-Golden M, Penke LR, Wolf B, Hardiman G, Langefeld CD, Medsger TA, Feghali-Bostwick CA. Antifibrotic factor KLF4 is repressed by the miR-10/TFAP2A/TBX5 axis in dermal fibroblasts: insights from twins discordant for systemic sclerosis. Ann Rheum Dis. 2021 Nov 08; doi: 10.1136/annrheumdis-2021-221050. Epub 2021 Nov 08. PMID: 34750102.
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Ann Rheum Dis. 2021 Nov 08; doi: 10.1136/annrheumdis-2021-221050. Epub 2021 Nov 08.

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

Annals of the rheumatic diseases

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

Affiliations

  1. Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
  2. Biostatistical Sciences and Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
  3. School of Biological Sciences, Institute for Global Food Security, Queen's University Belfast, Belfast, UK.
  4. Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA.
  5. Science, Bay Path University, Longmeadow, Massachusetts, USA.
  6. Internal Medicine, University of Michigan Michigan Medicine, Ann Arbor, Michigan, USA.
  7. Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
  8. Medicine, Medical University of South Carolina, Charleston, South Carolina, USA [email protected].

PMID: 34750102 DOI: 10.1136/annrheumdis-2021-221050

Abstract

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 (

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.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Keywords: fibroblasts; scleroderma; systemic; systemic sclerosis

Conflict of interest statement

Competing interests: None declared.

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