Suv4-20h2 protects against influenza virus infection by suppression of chromatin loop formation

Masami Shiimori; Yu Ichida; Ryota Nukiwa; Toshie Sakuma; Haruka Abe; Rei Kajitani; Yuji Fujino; Akira Kikuchi; Takeshi Kawamura; Tatsuhiko Kodama; Shinichi Toyooka; Katsuhiko Shirahige; Gunnar Schotta; Keiji Kuba; Takehiko Itoh; Yumiko Imai

doi:10.1016/j.isci.2021.102660

Suv4-20h2 protects against influenza virus infection by suppression of chromatin loop formation

iScience. 2021 May 29;24(6):102660. doi: 10.1016/j.isci.2021.102660. eCollection 2021 Jun 25.

Authors

Masami Shiimori¹, Yu Ichida¹, Ryota Nukiwa^{1

2}, Toshie Sakuma¹, Haruka Abe¹, Rei Kajitani³, Yuji Fujino², Akira Kikuchi⁴, Takeshi Kawamura^{5

6}, Tatsuhiko Kodama⁵, Shinichi Toyooka⁷, Katsuhiko Shirahige⁸, Gunnar Schotta⁹, Keiji Kuba¹⁰, Takehiko Itoh³, Yumiko Imai^{1

11}

Affiliations

¹ Laboratory of Regulation for Intractable Infectious Diseases, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka 567-0085, Japan.
² Department of Anesthesiology and Intensive Care Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
³ Department of Biological Information, School and Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Tokyo 152-8550, Japan.
⁴ Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
⁵ Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, the University of Tokyo, Tokyo 153-8904, Japan.
⁶ Proteomics Laboratory, Isotope Science Center, The University of Tokyo, Tokyo 113-0032, Japan.
⁷ Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Okayama 700-8558, Japan.
⁸ Laboratory of Genome Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo 113-0032, Japan.
⁹ Department of Molecular Biology, Biomedical Center, Ludwig-Maximilians-University, 82152 Munich, Germany; Munich Center for Integrated Protein Science (CiPS), 81377 Munich, Germany.
¹⁰ Department of Biochemistry and Metabolic Science, Akita University Faculty of Medicine, Akita 010-8543, Japan.
¹¹ Laboratory for Infectious Systems, Institute for Protein Research, Osaka University, Osaka 565-0871, Japan.

Abstract

The spatial organization of chromatin is known to be highly dynamic in response to environmental stress. However, it remains unknown how chromatin dynamics contributes to or modulates disease pathogenesis. Here, we show that upon influenza virus infection, the H4K20me3 methyltransferase Suv4-20h2 binds the viral protein NP, which results in the inactivation of Suv4-20h2 and the dissociation of cohesin from Suv4-20h2. Inactivation of Suv4-20h2 by viral infection or genetic deletion allows the formation of an active chromatin loop at the HoxC8-HoxC6 loci coincident with cohesin loading. HoxC8 and HoxC6 proteins in turn enhance viral replication by inhibiting the Wnt-β-catenin mediated interferon response. Importantly, loss of Suv4-20h2 augments the pathology of influenza infection in vivo. Thus, Suv4-20h2 acts as a safeguard against influenza virus infection by suppressing cohesin-mediated loop formation.

Keywords: Epigenetics; Molecular biology; Omics; Virology.