Article Text

Download PDFPDF
Extended report
Genome-wide DNA methylation analysis in dermal fibroblasts from patients with diffuse and limited systemic sclerosis reveals common and subset-specific DNA methylation aberrancies
  1. Nezam Altorok1,2,
  2. Pei-Suen Tsou1,3,
  3. Patrick Coit1,
  4. Dinesh Khanna1,3,
  5. Amr H Sawalha1,4
  1. 1Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
  2. 2Division of Rheumatology, Department of Internal Medicine, University of Toledo Medical Center, Toledo, Ohio, USA
  3. 3University of Michigan Scleroderma Program, Ann Arbor, Michigan, USA
  4. 4Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA
  1. Correspondence to Dr Amr H Sawalha, 1150 W. Medical Center Drive, 5520 MSRB-1, SPC 5680, Ann Arbor, MI 48109, USA; asawalha{at}


Background The aetiology of systemic sclerosis (SSc) is not clear, but there is an emerging evidence of gene-specific epigenetic dysregulation in the pathogenesis of SSc.

Methods We performed a genome-wide DNA methylation study in dermal fibroblasts in six diffuse cutaneous SSc (dSSc) patients, six limited cutaneous SSc (lSSc) patients compared with 12 age-matched, sex-matched and ethnicity-matched healthy controls. Cytosine methylation was quantified in more than 485 000 methylation sites across the genome. Differentially methylated CpG sites between patients and controls with a fold difference ≥1.2 were identified. Quantitative real-time RT-PCR was performed to assess correlation between DNA methylation changes and gene expression levels.

Results We identified 2710 and 1021 differentially methylated CpG sites in dSSc and lSSc, respectively. Of the differentially methylated sites, 61% in dSSc and 90% in lSSc were hypomethylated. There were only 203 CpG sites differentially methylated in both dSSc and lSSc, representing 118 hypomethylated and 6 hypermethylated genes. Common hypomethylated genes include ITGA9, encoding an α integrin. Other relevant genes such as ADAM12, COL23A1, COL4A2 and MYO1E, and transcription factors genes RUNX1, RUNX2 and RUNX3 were also hypomethylated in both dSSc and lSSc. Pathway analysis of differentially methylated genes in both dSSc and lSSc revealed enrichment of genes involved in extracellular matrix–receptor interaction and focal adhesion. We demonstrate significant correlation between DNA methylation status and gene expression in the majority of genes evaluated.

Conclusions Our data highlight common and subset-specific aberrancies in dSSc and lSSc fibroblasts at the epigenomic levels and identify novel candidate genes in SSc.

  • Systemic Sclerosis
  • Fibroblasts
  • Autoimmunity

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.