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. 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.
Neuroscience Section, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239, USA.
Dae-Hwan
DH
Kim
Neuroscience Section, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239, USA.
Janghyun
J
Kim
Neuroscience Section, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239, USA.
Ji-Sun
JS
Kwon
Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Jaspreet
J
Sandhu
Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Peter
P
Tontonoz
Neuroscience Section, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239, USA; Vollum Institute, Oregon Health and Science University, Portland, OR 97239, USA.
Soo-Kyung
SK
Lee
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 08826 Seoul, Korea. Electronic address: leeseung@snu.ac.kr.
Seunghee
S
Lee
Neuroscience Section, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239, USA. Electronic address: leejae@ohsu.edu.
Jae W
JW
Lee
D000818:Animals; D059305:Diet, High-Fat; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D000068877:Imatinib Mesylate / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D008820:Mice, Obese; D065626:Non-alcoholic Fatty Liver Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D047495:PPAR gamma / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics
D047495:PPAR gamma; D000068877:Imatinib Mesylate; D011495:Histone-Lysine N-Methyltransferase; C516439:MLL4 protein, mouse; D016315:Proto-Oncogene Proteins c-abl
ABL1; KMT2D; MLL4; NAFLD; PPAR gamma; UTX; fatty liver; imatinib