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

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. PPAR gamma 2 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 PPAR gamma 2. We demonstrate that overnutrition facilitates the recruitment of MLL4 to steatotic target genes of PPAR gamma 2 and their transactivation via H3 lysine 4 methylation because PPAR gamma 2 phosphorylated by overnutrition-activated ABL1 kinase shows enhanced interaction with MLL4. We further show that Ppar gamma 2 (encoding PPAR gamma 2) is also a hepatic target gene of ABL1-PPAR gamma 2-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-PPAR gamma 2-MLL4, which may serve as a target of anti-steatosis drug development.