Epigenetic regulation of DPP4 receptor expression by NONO enables replication of MERS-CoV

Middle East respiratory syndrome coronavirus (MERS-CoV), first reported in 2012, belongs to the Betacoronavirus genus, including SARS-CoV and SARS-CoV-2. Human-to-human transmission of MERS-CoV appears inefficient, but repeated spillover events have been reported from at least 27 countries, raising concern for future emergent events. Coronaviruses (CoVs) rely extensively on host proteins to support their replication. Several studies have implicated the paraspeckle non-POU domain-containing octamer-binding protein (NONO) as an RNA-binding protein (RBP) that binds to CoV genomes, but the role of this protein in regulating replication is unknown. Here, we show that NONO is required for expression of dipeptidyl peptidase 4 (DPP4, also known as CD26), the major cellular receptor required for MERS-CoV attachment and entry. NONO did not impact DPP4 mRNA processing or stability but instead promoted DPP4 transcription through control of active H3K4me3 and repressive H3K27me3 histone modifications at the DPP4 locus. Together, these findings identify NONO as a key proviral host factor for MERS-CoV and reveal an epigenetic mechanism linking a host RBP to viral entry receptor expression that may represent a target for therapeutic strategies.