Reduced chromatin accessibility to CD4 T cell super-enhancers encompassing susceptibility loci of rheumatoid arthritis
Rohit R. Jadhav,
Bin Hu,
Zhongde Ye,
Khushboo Sheth,
Xuanying Li,
William J. Greenleaf,
Cornelia M. Weyand,
Jörg J. Goronzy
Affiliations
Rohit R. Jadhav
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
Bin Hu
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
Zhongde Ye
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
Khushboo Sheth
Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA
Xuanying Li
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
William J. Greenleaf
Department of Genetics, Stanford University, Stanford, CA, United States
Cornelia M. Weyand
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
Jörg J. Goronzy
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; Address correspondence to: Jörg J. Goronzy, M.D., Ph.D., Department of Immunology, Mayo Clinic, Guggenheim Building 4-21, 222 3rd Ave SW, Rochester, MN 55905; telephone (507) 774-5617.
Summary: 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.
