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Latent infections are necessary for both persistent lifelong MDV infection and viral tumorigenesis. MicroRNAs (miRNAs) play critical roles as post-transcriptional regulators of viral infections. However, the role of miRNAs in regulating MDV latency remains unclear. In this study, we found that an MDV-encoded miRNA, miR-M6-5p, inhibited viral lytic replication\n              <jats:italic>in vitro<\/jats:italic>\n              by functional screening and that infection with an MDV mutant lacking miR-M6-5p resulted in impaired MDV latency, proliferation, and tumor formation\n              <jats:italic>in vivo<\/jats:italic>\n              . Importantly, we identified lysine-specific demethylase 2b (KDM2B), an important epigenetic factor, as a target of miR-M6-5p. Furthermore, KDM2B knockdown increased the level of the transcriptionally repressive histone mark H3K27me3 on the key lytic gene pp38 promoter, accompanied by suppression of pp38 expression and reduced latent-to-lytic switch in MDV-latently infected cells, while treatment of cells with H3K27me3 inhibitors (GSK126 and Tazemetostat) markedly promoted the expression of pp38 and MDV reactivation from latency. Thus, miR-M6-5p facilitates MDV latency by epigenetically suppressing pp38 expression by targeting KDM2B. These \ufb01ndings unravel the mechanism by which a virus-encoded miRNA plays a critical role in the regulation of latent MDV infection.\n            <\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>\n                Similar to other herpesviruses, MDV can establish a lifelong latent infection in the host. During the latency, MDV integrates its genome into the host genome to maintain the viral genome, which is considered a prerequisite for tumor formation. Reactivation of the latent viral genome in response to intracellular and extracellular stimuli re-enters lytic replication, resulting in pathological recurrence and\/or viral shedding. However, the regulatory mechanisms underlying MDV latency remain poorly understood. In the present study, we investigated the role of virus-encoded miRNAs in MDV latency. We found that miR-M6-5p facilitated MDV latency, proliferation, and tumor formation\n                <jats:italic>in vivo<\/jats:italic>\n                . Mechanistically, miR-M6-5p epigenetically suppressed the expression of the viral lytic gene pp38 by directly targeting the histone demethylase KDM2B. These \ufb01ndings will advance our understanding of the role of virus-encoded miRNA in the regulation of viral latency and will help guide the development of novel strategies for the effective control of MDV.\n              <\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/jvi.02007-24","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T14:00:37Z","timestamp":1737554437000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":4,"title":["Marek\u2019s disease virus-encoded microRNA-M6-5p facilitates viral latent infection by targeting histone demethylase KDM2B"],"prefix":"10.1128","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-6876-9337","authenticated-orcid":false,"given":"Linyi","family":"Zhou","sequence":"first","affiliation":[{"name":"Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agriculture and Forestry 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