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

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 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. Therefore, 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. This article is protected by copyright. All rights reserved.

The Hippocampal Response to Acute Corticosterone Elevation Is Altered in a Mouse Model for Angelman Syndrome

“…However, continuous CORT exposure did lead to a statistical interaction between AS and CORT treatment in the liver transcriptome, which suggests that UBE3A may regulate GR activity in a tissue-specific manner. The observed changes in the liver transcriptomic response to continuous CORT treatment are in line with AS mice susceptibility to hepatic dysfunction [34].…”

“…Disrupted GR signaling in the hippocampus of UBE3A-deficient AS mice has been associated with learning disabilities and anxiety-like behavior [33]. Furthermore, UBE3A-deficient AS mice are known to be hypersensitive to diet-induced liver steatosis [34], and previously showed metabolic disturbances resulting from an altered circadian rhythm [35]; characteristics that have been related to disruptions in GR signaling [36][37][38]. However, the molecular mechanisms underlying the UBE3A modulation of GR signaling are not fully understood.…”

Identification and Evaluation of Hub Long Noncoding RNAs and mRNAs in High Fat Diet Induced Liver Steatosis

“…MLL4 was defined as a critical regulator of overnutrition that induced obesity and hepatic steatosis [ 50 ]. Moreover, Ube3a suppressed overnutrition-induced NAFLD by targeting and degrading MLL4 [ 51 ]. Calcoco1, Smarca2, Cln3, Tacc1, and Gm38366 were coexpressed with Lpin1 and Ube3a.…”

Effects of UBE3A on Cell and Liver Metabolism through the Ubiquitination of PDHA1 and ACAT1

“…While much effort has been devoted to studying the transcriptional regulation of metabolic pathways during the development of hepatic steatosis, little is known about the post-translational modification of metabolic enzymes in this process, especially through ubiquitination-mediated mechanisms. Therefore, we employed a unique approach based on the OUT platform to identify the metabolic enzymes as ubiquitination targets of UBE3A, which has been shown to prevent HFD-induced hepatic steatosis in mice . We further verified the ubiquitination of PDHA1 and ACAT1 by UBE3A in HEK293 cells and studied the physiological role of UBE3A in regulating the stabilities of its substrate proteins and lipid metabolism in vivo.…”

“…Due to genomic imprinting, the Ube3a gene is paternally inactivated in the brain, so its UB ligase activity is vulnerable to mutations in the maternal copy of the gene that may render the gene defective and cause the delay of neuronal and intellectual development in children. , On the other hand, the duplication of the Ube3a gene in the maternal chromosome is associated with autism spectrum disorders. , Ube3a is normally expressed from both paternal and maternal copies of the chromosome in the peripheral tissues. The binding of the E6 protein of the human papillomavirus (HPV) with UBE3A would induce the degradation of the tumor suppressor p53, which is causative for the development of cervical cancer. , UBE3A has been recently shown to play a role in hepatic steatosis . In this study, we identified two essential enzymes regulating glycolysis, the TCA cycle, and ketogenesis, namely pyruvate dehydrogenase A1 (PDHA1) and acetyl-CoA acetyltransferase 1 (ACAT1), as ubiquitination targets of UBE3A.…”