Suv4-20h2 protects from influenza virus infection through suppression of chromatin loop structure

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 modulate the disease pathogenesis. Here we show that upon influenza virus infection, H4K20me3 methyltransferase Suv4-20h2 binds the viral protein NP, which results in the inactivation of the Suv4-20h2 and the dissociation of cohesin from Suv4-20h2. Inactivation of Suv4-20h2 by virus infection or genetic deletion, leads to active loop formation at HoxC8-HoxC6 through the loading of cohesin to this region. HoxC8 and HoxC6 in turn enhance viral replication by inhibiting the Wnt-beta-catenin mediated interferon response. Importantly, loss of Suv4-20h2 augments the influenza pathology in vivo. Thus, Suv4-20h2 acts as a safeguard against influenza virus infection though the suppression of a cohesin-mediated loop formation.

已知染色质的空间构象在响应环境胁迫时具有高度动态性。然而，染色质动态变化如何参与或调控疾病发病机制，目前仍不明朗。本研究发现，在流感病毒感染过程中，H4K20me3甲基转移酶Suv4-20h2会与病毒蛋白NP结合，导致Suv4-20h2失活，并使黏连蛋白（cohesin）从Suv4-20h2上解离。通过病毒感染或基因敲除使Suv4-20h2失活后，黏连蛋白会被招募至HoxC8-HoxC6区域，进而激活该区域的染色质环形成。HoxC8与HoxC6则可通过抑制Wnt-β-连环蛋白介导的干扰素应答，促进病毒复制。值得注意的是，在体内实验中，Suv4-20h2的缺失会加剧流感病毒引发的病理损伤。综上，Suv4-20h2可通过抑制黏连蛋白介导的染色质环形成，发挥抵御流感病毒感染的保护作用。