The pathophysiologic continuum of non-alcoholic fatty liver disease begins with steatosis. Despite great progress in understanding the gene regulatory program directing steatosis, how it is orchestrated epigenetically is unclear. Here we show that the histone H3-lysine-4-methyltransferase, MLL4/KMT2D, plays critical roles in overnutrition-induced murine steatosis via dual mechanisms. First, in response to high fat diet (HFD), MLL4 activates the expression of PPAR2, an overnutrition-induced steatotic transcription factor. Second, HFD enables the coactivator function of MLL4 for PPAR2, asovernutrition-activated ABL1 kinase phosphorylates PPAR2 and enhances its association with MLL4, facilitating recruitment of MLL4 to steatotic target genes of PPAR2, including the PPAR2-encoding gene itself, and their transactivation via H3-lysine-4-methylation. Consistently,inhibition of ABL1 improves the fatty liver condition ofob/obmice bysuppressing the pro-steatotic action of MLL4. Our results uncover a critical regulatory axis in overnutrition-directed steatosis, and present this ABL1-PPAR2-MLL4 axis as a new target for anti-steatosis drug development. SOURCE: Jae,W,Lee (leejae@ohsu.edu) -  Oregon Health & Science University

Pluto Bioinformatics

GSE83940: Critical Roles of the Histone Methyltransferase MLL4/KMT2D in Murine Hepatic Steatosis Directed by ABL1 and PPAR2