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The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s

Author

Listed:
  • Hale Tunbak

    (Queen Mary University of London)

  • Rocio Enriquez-Gasca

    (Queen Mary University of London)

  • Christopher H. C. Tie

    (University College London)

  • Poppy A. Gould

    (Queen Mary University of London)

  • Petra Mlcochova

    (University of Cambridge)

  • Ravindra K. Gupta

    (University of Cambridge)

  • Liane Fernandes

    (Queen Mary University of London)

  • James Holt

    (Queen Mary University of London)

  • Annemarthe G. Veen

    (The Francis Crick Institute
    Leiden University Medical Centre, Department of Immunohematology and Blood Transfusion)

  • Evangelos Giampazolias

    (The Francis Crick Institute)

  • Kathleen H. Burns

    (John Hopkins University School of Medicine)

  • Pierre V. Maillard

    (Queen Mary University of London)

  • Helen M. Rowe

    (Queen Mary University of London)

Abstract

The Human Silencing Hub (HUSH) complex is necessary for epigenetic repression of LINE-1 elements. We show that HUSH-depletion in human cell lines and primary fibroblasts leads to induction of interferon-stimulated genes (ISGs) through JAK/STAT signaling. This effect is mainly attributed to MDA5 and RIG-I sensing of double-stranded RNAs (dsRNAs). This coincides with upregulation of primate-conserved LINE-1s, as well as increased expression of full-length hominid-specific LINE-1s that produce bidirectional RNAs, which may form dsRNA. Notably, LTRs nearby ISGs are derepressed likely rendering these genes more responsive to interferon. LINE-1 shRNAs can abrogate the HUSH-dependent response, while overexpression of an engineered LINE-1 construct activates interferon signaling. Finally, we show that the HUSH component, MPP8 is frequently downregulated in diverse cancers and that its depletion leads to DNA damage. These results suggest that LINE-1s may drive physiological or autoinflammatory responses through dsRNA sensing and gene-regulatory roles and are controlled by the HUSH complex.

Suggested Citation

  • Hale Tunbak & Rocio Enriquez-Gasca & Christopher H. C. Tie & Poppy A. Gould & Petra Mlcochova & Ravindra K. Gupta & Liane Fernandes & James Holt & Annemarthe G. Veen & Evangelos Giampazolias & Kathlee, 2020. "The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19170-5
    DOI: 10.1038/s41467-020-19170-5
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    Cited by:

    1. Ahmad Luqman-Fatah & Yuzo Watanabe & Kazuko Uno & Fuyuki Ishikawa & John V. Moran & Tomoichiro Miyoshi, 2023. "The interferon stimulated gene-encoded protein HELZ2 inhibits human LINE-1 retrotransposition and LINE-1 RNA-mediated type I interferon induction," Nature Communications, Nature, vol. 14(1), pages 1-26, December.
    2. Qin Yu & Alba Herrero del Valle & Rahul Singh & Yorgo Modis, 2021. "MDA5 disease variant M854K prevents ATP-dependent structural discrimination of viral and cellular RNA," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    3. Bert I. Crawford & Mary Jo Talley & Joshua Russman & James Riddle & Sabrina Torres & Troy Williams & Michelle S. Longworth, 2024. "Condensin-mediated restriction of retrotransposable elements facilitates brain development in Drosophila melanogaster," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Ninoslav Pandiloski & Vivien Horváth & Ofelia Karlsson & Symela Koutounidou & Fereshteh Dorazehi & Georgia Christoforidou & Jon Matas-Fuentes & Patricia Gerdes & Raquel Garza & Marie E. Jönsson & Anit, 2024. "DNA methylation governs the sensitivity of repeats to restriction by the HUSH-MORC2 corepressor," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    5. Tiantian Jing & Dianhui Wei & Xiaoli Xu & Chengsi Wu & Lili Yuan & Yiwen Huang & Yizhen Liu & Yanyi Jiang & Boshi Wang, 2024. "Transposable elements-mediated recruitment of KDM1A epigenetically silences HNF4A expression to promote hepatocellular carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-21, December.

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