Kim, Janghyun Lee, Bora Kim, Dae-Hwan Yeon, Jae Gwang Lee, Jeongkyung Park, Younjung Lee, Yuna Lee, Soo-Kyung Lee, Seunghee Lee, Jae W. 2024-01-19T20:33:05Z 2024-01-19T20:33:05Z 2021-09-02 2019-03 0270-9139 https://pubs.kist.re.kr/handle/201004/120272 Regulation of the protein stability of epigenetic regulators remains ill-defined despite its potential applicability in epigenetic therapies. The histone H3-lysine 4-methyltransferase MLL4 is an epigenetic transcriptional coactivator that directs overnutrition-induced obesity and fatty liver formation, and Mll4+/- mice are resistant to both. Here we show that the E3 ubiquitin ligase UBE3A targets MLL4 for degradation, thereby suppressing high-fat diet (HFD)-induced expression of the hepatic steatosis target genes of MLL4. In contrast to Mll4+/- mice, Ube3a+/- mice are hypersensitive to HFD-induced obesity and fatty liver development. Ube3a+/-;Mll4+/- mice lose this hypersensitivity, supporting roles of increased MLL4 levels in both phenotypes of Ube3a+/- mice. Correspondingly, our comparative studies with wild-type, Ube3a+/- and Ube3a-/- and UBE3A-overexpressing transgenic mouse livers demonstrate an inverse correlation of UBE3A protein levels with MLL4 protein levels, expression of the steatosis target genes of MLL4, and their decoration by H3-lysine 4-monomethylation, a surrogate marker for the epigenetic action of MLL4. Conclusion: UBE3A indirectly exerts an epigenetic regulation of obesity and steatosis by degrading MLL4. This UBE3A-MLL4 regulatory axis provides a potential therapeutic venue for treating various MLL4-directed pathogeneses, including obesity and hepatic steatosis. English WILEY ACTIVATING SIGNAL COINTEGRATOR-2 LIVER-X-RECEPTORS UBIQUITIN LIGASE TRANSCRIPTIONAL COACTIVATOR DROSOPHILA HOMOLOG HEPATIC STEATOSIS PROTEIN ROLES P53 HOMEOSTASIS UBE3A Suppresses Overnutrition-Induced Expression of the Steatosis Target Genes of MLL4 by Degrading MLL4 Article 10.1002/hep.30284 1 HEPATOLOGY, v.69, no.3, pp.1122 - 1134 HEPATOLOGY 69 3 1122 1134 scie scopus 000459816500017 2-s2.0-85061229122 Gastroenterology & Hepatology Gastroenterology & Hepatology Article ACTIVATING SIGNAL COINTEGRATOR-2 LIVER-X-RECEPTORS UBIQUITIN LIGASE TRANSCRIPTIONAL COACTIVATOR DROSOPHILA HOMOLOG HEPATIC STEATOSIS PROTEIN ROLES P53 HOMEOSTASIS