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Department of Immunology, Mayo Clinic School of Medicine and Sciences, Rochester, MN, United States; Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, United States; Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA; Division of Rheumatology, Department of Medicine, Mayo Clinic School of Medicine and Sciences, Rochester, MN, United States. Electronic address:
Published: February 2022
AI Article Synopsis
Article Abstract
Background: 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.
Methods: 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.
Findings: 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.
Interpretation: Disease-associated genes are epigenetically less poised to respond in CD4 T cells from patients with established RA.
Funding: This work was supported by I01 BX001669 from the Veterans Administration.
