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Antifibrotic factor KLF4 is repressed by the miR-10/TFAP2A/TBX5 axis in dermal fibroblasts: insights from twins
Maya Malaab1, Ludivine Renaud1, Naoko Takamura1
1Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
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.
Insights
Epigenetic changes in dermal fibroblasts contribute to systemic sclerosis (SSc) development. Reduced KLF4 expression, driven by other transcription factors, promotes fibrosis, suggesting epigenetic modifiers as potential SSc therapies.
Area of Science:
- Molecular biology
- Epigenetics
- Dermatology
Background:
- Systemic sclerosis (SSc) is a fibrotic disease with no effective treatments.
- Understanding SSc pathogenesis is crucial for developing new therapies.
Purpose of the Study:
- To identify molecular features and epigenetic dysregulation in SSc dermal fibroblasts.
- To uncover potential therapeutic targets for SSc.
Main Methods:
- Global gene expression and DNA methylation analysis of SSc-discordant twin dermal fibroblasts (dFBs).
- Validation using in vitro, ex vivo, and in vivo models.
Main Results:
- Identified differentially expressed and methylated genes, including transcription factors (KLF4, TBX5, TFAP2A) and microRNAs (miR-10a, miR-10b).
- KLF4 expression is reduced in SSc dFBs, repressed by TBX5 and TFAP2A.
- KLF4 is antifibrotic; its knockout promotes a fibrotic phenotype.
Conclusions:
- Epigenetic dysregulation plays a role in SSc susceptibility.
- Highlights interplay between methylation, miRNAs, and transcription factors in SSc.
- Suggests epigenetic modifiers as potential SSc therapies.
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