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However, the epigenetic mechanism underlying chondrogenesis in DPSCs remains elusive. Herein, it is demonstrated that KDM3A and G9A, an antagonistic pair of histone\u2010modifying enzymes, bidirectionally regulate the chondrogenic differentiation of DPSCs by controlling SOX9 (sex\u2010determining region Y\u2010type high\u2010mobility group box protein 9) degradation through lysine methylation. Transcriptomics analysis reveals that KDM3A is significantly upregulated during the chondrogenic differentiation of DPSCs. In vitro and in vivo functional analyses further indicate that KDM3A promotes chondrogenesis in DPSCs by boosting the SOX9 protein level, while G9A hinders the chondrogenic differentiation of DPSCs by reducing the SOX9 protein level. Furthermore, mechanistic studies indicate that KDM3A attenuates the ubiquitination of SOX9 by demethylating lysine (K) 68 residue, which in turn enhances SOX9 stability. Reciprocally, G9A facilitates SOX9 degradation by methylating K68 residue to increase the ubiquitination of SOX9. Meanwhile, BIX\u201001294 as a highly specific G9A inhibitor significantly induces the chondrogenic differentiation of DPSCs. These findings provide a theoretical basis to ameliorate the clinical use of DPSCs in cartilage tissue\u2010engineering therapies.<\/jats:p>","DOI":"10.1002\/advs.202206757","type":"journal-article","created":{"date-parts":[[2023,6,30]],"date-time":"2023-06-30T02:23:31Z","timestamp":1688091811000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Lysine 68 Methylation\u2010Dependent SOX9 Stability Control Modulates Chondrogenic Differentiation in Dental Pulp Stem Cells"],"prefix":"10.1002","volume":"10","author":[{"given":"Qiannan","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Orthodontics Peking University School and Hospital of Stomatology  Beijing 100081 China"},{"name":"National Center of Stomatology &amp; National Clinical Research Center for Oral Diseases &amp; National Engineering Laboratory for Digital and Material Technology of Stomatology &amp; Beijing Key Laboratory for Digital 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