Reduced chromatin accessibility to CD4 T cell super-enhancers encompassing susceptibility loci of rheumatoid arthritis

• Published in: EBioMedicine 2022-02, Vol.76, p.103825-103825, Article 103825
• Main Authors: Jadhav, Rohit R., Hu, Bin, Ye, Zhongde, Sheth, Khushboo, Li, Xuanying, Greenleaf, William J., Weyand, Cornelia M., Goronzy, Jörg J.
• Format: Article
• Language: English
• Subjects: Arthritis, Rheumatoid - genetics; CD4-Positive T-Lymphocytes; Chromatin - genetics; Chromatin accessibility; DNA Methylation; Epigenome; Humans; Regulatory Sequences, Nucleic Acid; Rheumatoid arthritis; Super-enhancer; Susceptibility loci
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2022.103825

Rheumatoid arthritis (RA) is an inflammatory disease that manifests as a preclinical stage of systemic autoimmunity followed by chronic progressive synovitis. Disease-associated genetic SNP variants predominantly map to non-coding, regulatory regions of functional importance in CD4 T cells, implicating these cells as key regulators. A better understanding of the epigenome of CD4 T cells holds the promise of providing information on the interaction between genetic susceptibility and exogenous factors. We mapped regions of chromatin accessibility using ATAC-seq in peripheral CD4 T cell subsets of patients with RA (n=18) and compared them to T cells from patients with psoriatic arthritis (n=11) and age-matched healthy controls (n=10). Transcripts of selected genes were quantified using qPCR. RA-associated epigenetic signatures were identified that in part overlapped between central and effector memory CD4 T cells and that were to a lesser extent already present in naïve cells. Sites more accessible in RA were highly enriched for the motif of the transcription factor (TF) CTCF suggesting differences in the three-dimensional chromatin structure. Unexpectedly, sites with reduced chromatin accessibility were enriched for motifs of TFs pertinent for T cell function. Most strikingly, super-enhancers encompassing RA-associated SNPs were less accessible. Analysis of selected transcripts and published DNA methylation patterns were consistent with this finding. The preferential loss in accessibility at these super-enhancers was seen in patients with high and low disease activity and on a variety of immunosuppressive treatment modalities. Disease-associated genes are epigenetically less poised to respond in CD4 T cells from patients with established RA. This work was supported by I01 BX001669 from the Veterans Administration.