The E3 Ubiquitin Ligase UBE3A Antagonizes Steatosis by Targeting the Pro-Steatotic Epigenetic Regulator MLL4 for Degradation

Regulation of the stability of epigenetic regulators offers unique opportunities for epigenetic therapies. However, this strategy has been poorly explored. Here we report that the E3 ubiquitin ligase UBE3A binds and ubiquitylates the histone H3-lysine 4-methyltransferase MLL4 (aka KMT2D) as a new substrate for degradation. Using Ube3a knockout and UBE3A-overexpressing transgenic mouse models, we show that, in the liver, UBE3A levels are inversely correlated with levels of MLL4, its functional surrogate marker H3-lysine 4-monomethylation, and expression of the recently identified steatosis target genes of MLL4. Consistently, Ube3a knockout mice are highly susceptible to high-fat diet-induced steatosis relative to their littermate control mice, and this phenotype is rescued by deletion of a copy of Mll4. Therefore, UBE3A indirectly exerts an epigenetic gene regulation activity through targeting MLL4 for degradation. Also this UBE3A-MLL4 axis presents a novel therapeutic venue for treating various MLL4-directed pathogeneses. RNA samples from wild-type and Ube3a het or Ube3a TG homo livers treated with high-fat diet were prepared for sequencing according to the Illumina protocol, and sequenced on the Illumina HiSeq 2500. We then compared the transcriptome changes between WT and Ube3a het or TG livers after high-fat diet. And then we identified gene whose expression is altered by high-fat diet in Ube3a mutant liver compared to wild-type. The Ube3a TG homo samples overexpress Ube3a. The Ube3a het samples have one knockout and one wt allele, so they express half amount of Ube3a.