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

Abstract

Summary 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.

Dynamics of Viral and Host 3D Genome Structure upon Infection

“…The molecular mechanisms employed by RNA viruses, which are typically limited to acute infection, are likely varied but may still converge on common host architectural factors, such as CTCF and cohesin. Indeed, recent evidence suggests that IAV and SARS-CoV-2 infections can perturb CTCF and/or cohesin distribution to cause alterations in host chromosomal topology [ 83 , 84 , 93 ], while CTCF/cohesin-dependent host genome organization may contribute to the pathology associated with these RNA viruses [ 86 , 88 ]. Nevertheless, further investigation is needed to elucidate the mechanistic details by which non-integrating RNA viruses affect host chromatin architecture to modulate gene expression and promote disease.…”

“…2F , left). Another study, using 4C-seq and DNA FISH data, reported an alternative viral strategy targeting cohesin, which is mediated by the IAV protein NP and impacts host chromosomal organization to enhance viral replication [ 84 ]. In this scenario, the viral protein NP binds to the host histone H4 methyltransferase Suv4-20h2, disrupting the association of the latter with cohesin.…”

Viral remodeling of the 4D nucleome

“…In the context of integrating viruses such as human T-lymphotropic virus type 1 (HTLV), human immunodeficiency virus (HIV), and HPV, insertion of ectopic viral DNA into host chromosomes has been shown to alter cellular genomic loops and TAD structures 32 – 38 . Host 3D genome changes have also been observed for several viruses that do not interact with their host nuclear genome, such as SARS-CoV-2 and influenza A viruses, but modulate 3D genome changes through the action of viral proteins and other unidentified factors that are yet to be fully understood 39 – 41 (Fig. 1c, d ).…”

“…For example, the influenza A protein NP interacts with the histone methyltransferase Suv4‒20h2, resulting in the inactivation of Suv4‒20h2 and subsequent dissociation of cohesin. This, in turn, allows cohesin to mediate the active loop formation of HoxC8‒HoxC6, leading to increased expression of HoxC8 and HoxC6 41 . In response, the HoxC8 and HoxC6 proteins boost viral replication by inhibiting the Wnt-β-catenin-mediated interferon response 94 , 95 .…”

Comprehensive multiomics analyses reveal pervasive involvement of aberrant cohesin binding in transcriptional and chromosomal disorder of cancer cells

“… 10 Cohesin, a ring-shaped chromosome-bound protein complex, is one such factor that fundamentally controls chromatin structure and transcription. 11 , 12 …”