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
Affiliations
Dae-Hwan Kim
Neuroscience Section, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239, USA
Janghyun Kim
Neuroscience Section, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239, USA
Ji-Sun Kwon
Neuroscience Section, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239, USA
Jaspreet Sandhu
Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA
Peter Tontonoz
Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA
Soo-Kyung Lee
Neuroscience Section, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239, USA
Seunghee Lee
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 08826 Seoul, Korea
Jae W. Lee
Neuroscience Section, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239, USA
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.
