| First Author | Kim DH | Year | 2016 |
| Journal | Cell Rep | Volume | 17 |
| Issue | 6 | Pages | 1671-1682 |
| PubMed ID | 27806304 | Mgi Jnum | J:242336 |
| Mgi Id | MGI:5904928 | Doi | 10.1016/j.celrep.2016.10.023 |
| Citation | Kim DH, et al. (2016) Critical Roles of the Histone Methyltransferase MLL4/KMT2D in Murine Hepatic Steatosis Directed by ABL1 and PPARgamma2. Cell Rep 17(6):1671-1682 |
| abstractText | 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. PPARgamma2 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 PPARgamma2. We demonstrate that overnutrition facilitates the recruitment of MLL4 to steatotic target genes of PPARgamma2 and their transactivation via H3 lysine 4 methylation because PPARgamma2 phosphorylated by overnutrition-activated ABL1 kinase shows enhanced interaction with MLL4. We further show that Pparg2 (encoding PPARgamma2) is also a hepatic target gene of ABL1-PPARgamma2-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-PPARgamma2-MLL4, which may serve as a target of anti-steatosis drug development. |
