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Interferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in Systemic Lupus Erythematosus

Author

Listed:
  • Christopher A. Odhams

    (King’s College London
    Queen Mary University of London)

  • Amy L. Roberts

    (King’s College London
    King’s College London)

  • Susan K. Vester

    (King’s College London)

  • Carolina S. T. Duarte

    (King’s College London)

  • Charlie T. Beales

    (King’s College London)

  • Alexander J. Clarke

    (University of Oxford)

  • Sonja Lindinger

    (King’s College London
    University of Applied Sciences - FH Campus Wien
    Johannes Kepler University Linz)

  • Samuel J. Daffern

    (King’s College London
    University of Cambridge)

  • Antonino Zito

    (King’s College London)

  • Lingyan Chen

    (King’s College London
    University of Cambridge)

  • Leonardo L. Jones

    (King’s College London)

  • Lora Boteva

    (King’s College London
    University of Edinburgh Western General Hospital)

  • David L. Morris

    (King’s College London)

  • Kerrin S. Small

    (King’s College London)

  • Michelle M. A. Fernando

    (King’s College London)

  • Deborah S. Cunninghame Graham

    (King’s College London)

  • Timothy J. Vyse

    (King’s College London)

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease, characterised by increased expression of type I interferon (IFN)-regulated genes and a striking sex imbalance towards females. Through combined genetic, in silico, in vitro, and ex vivo approaches, we define CXorf21, a gene of hitherto unknown function, which escapes X-chromosome inactivation, as a candidate underlying the Xp21.2 SLE association. We demonstrate that CXorf21 is an IFN-response gene and that the sexual dimorphism in expression is magnified by immunological challenge. Fine-mapping reveals a single haplotype as a potential causal cis-eQTL for CXorf21. We propose that expression is amplified through modification of promoter and 3′-UTR chromatin interactions. Finally, we show that the CXORF21 protein colocalises with TLR7, a pathway implicated in SLE pathogenesis. Our study reveals modulation in gene expression affected by the combination of two hallmarks of SLE: CXorf21 expression increases in a both an IFN-inducible and sex-specific manner.

Suggested Citation

  • Christopher A. Odhams & Amy L. Roberts & Susan K. Vester & Carolina S. T. Duarte & Charlie T. Beales & Alexander J. Clarke & Sonja Lindinger & Samuel J. Daffern & Antonino Zito & Lingyan Chen & Leonar, 2019. "Interferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in Systemic Lupus Erythematosus," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10106-2
    DOI: 10.1038/s41467-019-10106-2
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    Cited by:

    1. Andras Boeszoermenyi & Léa Bernaleau & Xudong Chen & Felix Kartnig & Min Xie & Haobo Zhang & Sensen Zhang & Maeva Delacrétaz & Anna Koren & Ann-Katrin Hopp & Vojtech Dvorak & Stefan Kubicek & Daniel A, 2023. "A conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Xudong Chen & Min Xie & Sensen Zhang & Marta Monguió-Tortajada & Jian Yin & Chang Liu & Youqi Zhang & Maeva Delacrétaz & Mingyue Song & Yixue Wang & Lin Dong & Qiang Ding & Boda Zhou & Xiaolin Tian & , 2023. "Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Chao Yang & Mahesh Bachu & Yong Du & Caroline Brauner & Ruoxi Yuan & Marie Dominique Ah Kioon & Giancarlo Chesi & Franck J. Barrat & Lionel B. Ivashkiv, 2022. "CXCL4 synergizes with TLR8 for TBK1-IRF5 activation, epigenomic remodeling and inflammatory response in human monocytes," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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