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

ABSTRACT: 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 PPARγ2, an overnutrition-induced steatotic transcription factor. Second, HFD enables the coactivator function of MLL4 for PPARγ2, as overnutrition-activated ABL1 kinase phosphorylates PPARγ2 and enhances its association with MLL4, facilitating recruitment of MLL4 to steatotic target genes of PPARγ2, including the PPARγ2-encoding gene itself, and their transactivation via H3-lysine-4-methylation. Consistently, inhibition of ABL1 improves the fatty liver condition of ob/ob mice by suppressing the pro-steatotic action of MLL4. Our results uncover a critical regulatory axis in overnutrition-directed steatosis, and present this ABL1-PPARγ2-MLL4 axis as a new target for anti-steatosis drug development.

ORGANISM(S): Mus musculus

PROVIDER: GSE83940 | GEO | 2017/07/01

SECONDARY ACCESSION(S): PRJNA327495

REPOSITORIES: GEO

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

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