EZH2 enhances PCV2 replication through inhibition of MMP1 and MMP12 transcription activity

Porcine circovirus type 2 (PCV2), a single-stranded circular DNA virus, primarily targets the porcine immune system. It induces immunosuppression, subsequent porcine circovirus disease (PCVAD), causing substantial economic losses to the global swine industry. Enhancer of zeste homolog 2 (EZH2), a critical member of the polycomb group (PcG) protein family with histone methyltransferase activity, plays a significant role in epigenetic regulation. While previous studies have established EZH2’s role in viral infection and innate immune responses, its function in PCV2 infection remains unclear. In this study, we found that EZH2 overexpression promoted PCV2 infection, whereas EZH2 knockdown via specific small interfering RNA (siRNA) and inhibition of its activity reduced PCV2 infection. Furthermore, we identified EZH2-regulated downstream genes by RNA sequencing (RNA-seq) and found that MMP1 and MMP12 were significantly upregulated when EZH2 methyltransferase activity was inhibited by GSK126. Mechanistically, EZH2 overexpression repressed the promoters of MMP1 and MMP12, thereby facilitating PCV2 replication. Conversely, upon depletion of the EZH2 methyltransferase domain, inhibition of MMP1 and MMP12 promoters is lifted, thereby enabling MMP1 and MMP12 to suppress PCV2 replication. Our findings establish a link between the histone methyltransferase EZH2 and the PCV2 life cycle, advance understanding of the mechanisms underlying PCV2 infection, and suggest that drugs targeting MMP1/MMP12 activity may provide potential therapeutic approaches to prevent and control PCV2 infection and spread.