Janghyun Kim1, Bora Lee2, Dae-Hwan Kim1, Jae Gwang Yeon3, Jeongkyung Lee4, Younjung Park1, Yuna Lee1, Soo-Kyung Lee1,5, Seunghee Lee3, Jae W Lee1. 1. Neuroscience Section, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health & Science University, Portland, OR. 2. Center for Neuroscience, Korea Institute of Science and Technology, Seoul, Korea. 3. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea. 4. Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA. 5. Vollum Institute, Oregon Health & Science University, Portland, OR.
Abstract
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.
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.
Authors: Nathaniel D Heintzman; Rhona K Stuart; Gary Hon; Yutao Fu; Christina W Ching; R David Hawkins; Leah O Barrera; Sara Van Calcar; Chunxu Qu; Keith A Ching; Wei Wang; Zhiping Weng; Roland D Green; Gregory E Crawford; Bing Ren Journal: Nat Genet Date: 2007-02-04 Impact factor: 38.330
Authors: Young-Hwa Goo; Young Chang Sohn; Dae-Hwan Kim; Seung-Whan Kim; Min-Jung Kang; Dong-Ju Jung; Eunyee Kwak; Nickolai A Barlev; Shelley L Berger; Vincent T Chow; Robert G Roeder; David O Azorsa; Paul S Meltzer; Pan-Gil Suh; Eun Joo Song; Kong-Joo Lee; Young Chul Lee; Jae Woon Lee Journal: Mol Cell Biol Date: 2003-01 Impact factor: 4.272
Authors: Seunghee Lee; Dong-Kee Lee; Yali Dou; Jeongkyung Lee; Bora Lee; Eunyee Kwak; Young-Yun Kong; Soo-Kyung Lee; Robert G Roeder; Jae W Lee Journal: Proc Natl Acad Sci U S A Date: 2006-10-04 Impact factor: 11.205