UBE3A Suppresses Overnutrition-Induced Expression of the Steatosis Target Genes of MLL4 by Degrading MLL4

Janghyun Kim, Bora Lee, Dae Hwan Kim, Jae Gwang Yeon, Jeongkyung Lee, Younjung Park, Yuna Lee, Soo-Kyung Lee, Seunghee Lee, Jae Lee

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1122-1134
Number of pages13
JournalHepatology
Volume69
Issue number3
DOIs
StatePublished - Mar 1 2019

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Overnutrition
Epigenomics
Obesity
Genes
High Fat Diet
Fatty Liver
Lysine
Liver
Ubiquitin-Protein Ligases
Protein Stability
Methyltransferases
Histones
Transgenic Mice
Hypersensitivity
Proteins
Biomarkers
Phenotype
Therapeutics

ASJC Scopus subject areas

  • Hepatology

Cite this

UBE3A Suppresses Overnutrition-Induced Expression of the Steatosis Target Genes of MLL4 by Degrading MLL4. / Kim, Janghyun; Lee, Bora; Kim, Dae Hwan; Yeon, Jae Gwang; Lee, Jeongkyung; Park, Younjung; Lee, Yuna; Lee, Soo-Kyung; Lee, Seunghee; Lee, Jae.

In: Hepatology, Vol. 69, No. 3, 01.03.2019, p. 1122-1134.

Research output: Contribution to journalArticle

Kim, Janghyun ; Lee, Bora ; Kim, Dae Hwan ; Yeon, Jae Gwang ; Lee, Jeongkyung ; Park, Younjung ; Lee, Yuna ; Lee, Soo-Kyung ; Lee, Seunghee ; Lee, Jae. / UBE3A Suppresses Overnutrition-Induced Expression of the Steatosis Target Genes of MLL4 by Degrading MLL4. In: Hepatology. 2019 ; Vol. 69, No. 3. pp. 1122-1134.
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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.",
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