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Lupus enhancer risk variant causes dysregulation of IRF8 through cooperative lncRNA and DNA methylation machinery

Author

Listed:
  • Tian Zhou

    (Shanghai Jiao Tong University School of Medicine (SJTUSM)
    Shanghai Jiao Tong University School of Medicine (SJTUSM)
    Shenzhen Futian Hospital for Rheumatic Diseases)

  • Xinyi Zhu

    (Shanghai Jiao Tong University School of Medicine (SJTUSM))

  • Zhizhong Ye

    (Shenzhen Futian Hospital for Rheumatic Diseases)

  • Yong-Fei Wang

    (The University of Hong Kong)

  • Chao Yao

    (Chinese Academy of Sciences (CAS))

  • Ning Xu

    (Shanghai Jiao Tong University School of Medicine (SJTUSM))

  • Mi Zhou

    (Shanghai Jiao Tong University (SJTU))

  • Jianyang Ma

    (Shanghai Jiao Tong University School of Medicine (SJTUSM))

  • Yuting Qin

    (Shanghai Jiao Tong University School of Medicine (SJTUSM))

  • Yiwei Shen

    (Shanghai Jiao Tong University School of Medicine (SJTUSM))

  • Yuanjia Tang

    (Shanghai Jiao Tong University School of Medicine (SJTUSM))

  • Zhihua Yin

    (Shenzhen Futian Hospital for Rheumatic Diseases)

  • Hong Xu

    (Shanghai Jiao Tong University School of Medicine (SJTUSM)
    Shanghai Jiao Tong University School of Medicine (SJTUSM))

  • Yutong Zhang

    (Shanghai Jiao Tong University School of Medicine (SJTUSM))

  • Xiaoli Zang

    (Shanghai Jiao Tong University School of Medicine (SJTUSM))

  • Huihua Ding

    (Shanghai Jiao Tong University School of Medicine (SJTUSM))

  • Wanling Yang

    (The University of Hong Kong)

  • Ya Guo

    (Shanghai Jiao Tong University (SJTU))

  • John B. Harley

    (US Department of Veterans Affairs Medical Center)

  • Bahram Namjou

    (Cincinnati Children’s Hospital Medical Center)

  • Kenneth M. Kaufman

    (Cincinnati Children’s Hospital Medical Center
    Cincinnati Children’s Hospital Medical Center
    University of Cincinnati College of Medicine)

  • Leah C. Kottyan

    (Cincinnati Children’s Hospital Medical Center
    University of Cincinnati College of Medicine
    Cincinnati Children’s Hospital Medical Center)

  • Matthew T. Weirauch

    (Cincinnati Children’s Hospital Medical Center
    University of Cincinnati College of Medicine
    Cincinnati Children’s Hospital Medical Center
    Cincinnati Children’s Hospital Medical Center)

  • Guojun Hou

    (Shanghai Jiao Tong University School of Medicine (SJTUSM)
    Shanghai Jiao Tong University School of Medicine (SJTUSM)
    Shenzhen Futian Hospital for Rheumatic Diseases)

  • Nan Shen

    (Shanghai Jiao Tong University School of Medicine (SJTUSM)
    Shanghai Jiao Tong University School of Medicine (SJTUSM)
    Shenzhen Futian Hospital for Rheumatic Diseases
    Cincinnati Children’s Hospital Medical Center)

Abstract

Despite strong evidence that human genetic variants affect the expression of many key transcription factors involved in autoimmune diseases, establishing biological links between non-coding risk variants and the gene targets they regulate remains a considerable challenge. Here, we combine genetic, epigenomic, and CRISPR activation approaches to screen for functional variants that regulate IRF8 expression. We demonstrate that the locus containing rs2280381 is a cell-type-specific enhancer for IRF8 that spatially interacts with the IRF8 promoter. Further, rs2280381 mediates IRF8 expression through enhancer RNA AC092723.1, which recruits TET1 to the IRF8 promoter regulating IRF8 expression by affecting methylation levels. The alleles of rs2280381 modulate PU.1 binding and chromatin state to regulate AC092723.1 and IRF8 expression differentially. Our work illustrates an integrative strategy to define functional genetic variants that regulate the expression of critical genes in autoimmune diseases and decipher the mechanisms underlying the dysregulation of IRF8 expression mediated by lupus risk variants.

Suggested Citation

  • Tian Zhou & Xinyi Zhu & Zhizhong Ye & Yong-Fei Wang & Chao Yao & Ning Xu & Mi Zhou & Jianyang Ma & Yuting Qin & Yiwei Shen & Yuanjia Tang & Zhihua Yin & Hong Xu & Yutong Zhang & Xiaoli Zang & Huihua D, 2022. "Lupus enhancer risk variant causes dysregulation of IRF8 through cooperative lncRNA and DNA methylation machinery," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29514-y
    DOI: 10.1038/s41467-022-29514-y
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