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.