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

Dae-Hwan Kim,Janghyun Kim,Ji-Sun Kwon,Jaspreet Sandhu,Peter Tontonoz,Soo-Kyung Lee,Seunghee Lee,Jae W Lee

doi:10.1016/j.celrep.2016.10.023

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.

Highlights

Non-alcoholic fatty liver disease (NAFLD) shows a spectrum of liver pathology that resembles alcohol-induced fatty liver damage (Hardy et al, 2016)
In this report, using a combination of high-fat diet (HFD)-induced hepatic steatosis paradigm and unbiased genome-wide RNA sequencing (RNA-seq) analyses, we establish MLL4 as a critical regulator of overnutrition-induced hepatic steatosis. We demonstrate that this function of MLL4 is mainly mediated by PPARg2 because MLL4 preferentially binds to PPARg2 over PPARg1, likely via PPARg2-specific phosphorylation by HFDactivated ABL1 kinase in the liver
Resistance of Mll3/4 Mutant Mice to HFD-Induced Hepatic Steatosis We have reported previously that homozygous mutant mice expressing a catalytically inactive deletion form of MLL3, named Mll3D/D, are resistant to fatty liver formation induced by HFD (Lee et al, 2008a, 2008b)

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) shows a spectrum of liver pathology that resembles alcohol-induced fatty liver damage (Hardy et al, 2016). A subset of individuals with NAFLD develop non-alcoholic steatohepatitis (NASH), and some of these NASH patients eventually develop cirrhosis and/or liver cancer (Hardy et al, 2016). In line with the notion that NAFLD is a major health risk, numerous studies have been performed to obtain a better understanding of the epidemiology, etiology, pathophysiology, and therapeutic intervention of the disease. Triglyceride (TG) is an ester of three free fatty acids (FFAs) bound to glycerol, and the pathophysiologic continuum of NAFLD begins with accumulation of TGs within hepatocytes (i.e., hepatic steatosis). Despite great advances in our understanding of the gene regulatory program directing hepatic steatosis (Hardy et al, 2016), it is poorly understood how this program is orchestrated epigenetically

Results

Discussion

Conclusion