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In this study, inhibition of H3K27\u2010methylation (H3K27\u2010me3) by UNC1999 (H3K27\u2010methyltransferase inhibitor) was demonstrated to inhibit SARS\u2010CoV\u20102 replication, as evidenced by reduced levels of viral RNA\/protein. The m6A modifications of SARS\u2010CoV\u20102 RNA were predominantly present on the 3\u02b9 end, particularly the \u201cN\u201d gene. The methylated RNA immunoprecipitation (MeRIP) and western\u2010blot analysis revealed a negative correlation between levels of cellular H3K27\u2010me3 and m6A\u2010modifications on the SARS\u2010CoV\u20102 \u201cN\u201d gene. Moreover, m6A\u2010modifications of the SARS\u2010CoV\u20102 \u201cN\u201d gene were shown to promote the recruitment of YTHDF2, which eventually resulted in decay of the viral transcripts. The application of the H3K27\u2010demethyltransferase or KDM6A\/B inhibitor GSK\u2010J4 can restore H3K27\u2010me3 levels and mitigating the decay of viral mRNA in UNC1999\u2010treated SARS\u2010CoV\u20102\u2010infected cells. Furthermore, long\u2010term sequential passage (P\u2009=\u200950) of the virus in the presence of UNC1999 did not yield any UNC1999\u2010resistant SARS\u2010CoV\u20102 mutants. In conclusion, by integrating transcriptomics, molecular virology and functional analyses, we for the first time demonstrated that inhibition of H3K27\u2010me3 induces m6A\u2010mediated decay of SARS\u2010CoV\u20102 transcripts, highlighting UNC1999 as novel antiviral candidate against SARS\u2010CoV\u20102.<\/jats:p>","DOI":"10.1002\/jmv.70332","type":"journal-article","created":{"date-parts":[[2025,4,5]],"date-time":"2025-04-05T09:16:24Z","timestamp":1743844584000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["H3K27\u2010me3 Inhibition Induces YTHDF2\u2010Mediated Decay of m6A\u2010Marked Severe Acute Respiratory Syndrome Coronavirus 2 Transcripts"],"prefix":"10.1002","volume":"97","author":[{"given":"Ram","family":"Kumar","sequence":"first","affiliation":[{"name":"National Centre for Veterinary Type Cultures ICAR\u2010National Research Centre on Equines  Hisar 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