Critical Roles of the Histone Methyltransferase MLL4/KMT2D in Murine Hepatic Steatosis Directed by ABL1 and PPARγ2

Abstract

The pathophysiologic continuum of non-alcoholic fatty liver disease begins with steatosis. Despite recent advances in our understanding of the gene regulatory program directing steatosis, how it is orchestrated at the chromatin level is unclear. PPARγ2 is a hepatic steatotic transcription factor induced by overnutrition. Here, we report that the histone H3 lysine 4 methyltransferase MLL4/KMT2D directs overnutrition-induced murine steatosis via its coactivator function for PPARγ2. We demonstrate that overnutrition facilitates the recruitment of MLL4 to steatotic target genes of PPARγ2 and their transactivation via H3 lysine 4 methylation because PPARγ2 phosphorylated by overnutrition-activated ABL1 kinase shows enhanced interaction with MLL4. We further show that Pparg2 (encoding PPARγ2) is also a hepatic target gene of ABL1-PPARγ2-MLL4. Consistently, inhibition of ABL1 improves the fatty liver condition of mice with overnutrition by suppressing the pro-steatotic action of MLL4. Our results uncover a murine hepatic steatosis regulatory axis consisting of ABL1-PPARγ2-MLL4, which may serve as a target of anti-steatosis drug development.

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

“…The liver steatogenic function of MLL3/4 complexes involves their coactivator action for the lipogenic peroxisome proliferator‐activated receptor γ2 (PPARγ2) . Importantly, MLL3/4 decorate the enhancers with H3K4me1 and H3K4me2, and we have confirmed that MLL3/4‐complexes direct H3K4me1 modification of the enhancers associated with the lipogenic target genes of PPARγ2 and MLL3/4 …”

“…Obesity is common with Angelman syndrome, and Ube3a+/‐ mice, developed as an animal model for Angelman syndrome, also show obesity due to enhanced adipocity . Obesity is a major risk factor for nonalcoholic fatty liver disease, and indeed Mll4+/‐ mice are resistant to development of both obesity and hepatic steatosis . Here we report MLL4 as a new substrate of UBE3A.…”

“…ASC‐2, using its two LXXLL motifs that recognize the activated conformation of nuclear receptors, tethers MLL3/4 complexes to their target enhancers occupied by several nuclear receptors, triggering their target genes to form open chromatin for transactivation. Interestingly, epigenetic regulation of diverse metabolic processes has been identified as one of the key physiological functions of MLL3/4 complexes, including our recent report for their essential roles in overnutrition‐directed obesity and fatty liver formation . The liver steatogenic function of MLL3/4 complexes involves their coactivator action for the lipogenic peroxisome proliferator‐activated receptor γ2 (PPARγ2) .…”

Histone H3 lysine 4 methyltransferase KMT2D

“…Using RNA-Seq analysis, Kim et al revealed that KMT2C and KMT2D are key epigenetic regulators of the hepatic circadian clock and function as transcriptional coactivators of the circadian TFs retinoid-related orphan receptor (ROR)-α and -γ (Kim et al, 2015). The same group also showed that Kmt2d +/− mice exhibit resistance to high fat diet-induced hepatic steatosis (Kim et al, 2016). Consistent with the reported physical interactions between PPARγ and the KMT2D complex (Lee et al, 2008; Lee et al, 2013), KMT2D acts as a coactivator of PPARγ to direct over-nutrition induced steatosis in the mouse liver (Kim et al, 2016).…”

“…The same group also showed that Kmt2d +/− mice exhibit resistance to high fat diet-induced hepatic steatosis (Kim et al, 2016). Consistent with the reported physical interactions between PPARγ and the KMT2D complex (Lee et al, 2008; Lee et al, 2013), KMT2D acts as a coactivator of PPARγ to direct over-nutrition induced steatosis in the mouse liver (Kim et al, 2016). …”