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

Bibliographic Details
Title: Critical Roles of the Histone Methyltransferase MLL4/KMT2D in Murine Hepatic Steatosis Directed by ABL1 and PPARγ2
Authors: Dae-Hwan Kim, Janghyun Kim, Ji-Sun Kwon, Jaspreet Sandhu, Peter Tontonoz, Soo-Kyung Lee, Seunghee Lee, Jae W. Lee
Source: Cell Reports, Vol 17, Iss 6, Pp 1671-1682 (2016)
Publisher Information: Elsevier, 2016.
Publication Year: 2016
Collection: LCC:Biology (General)
Subject Terms: MLL4, KMT2D, UTX, NAFLD, fatty liver, PPAR gamma, ABL1, imatinib, Biology (General), QH301-705.5
More Details: 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.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 2211-1247
Relation: http://www.sciencedirect.com/science/article/pii/S2211124716314097; https://doaj.org/toc/2211-1247
DOI: 10.1016/j.celrep.2016.10.023
Access URL: https://doaj.org/article/18b9c449db374838bd542ea4be49b1e0
Accession Number: edsdoj.18b9c449db374838bd542ea4be49b1e0
Database: Directory of Open Access Journals
More Details
ISSN:22111247
DOI:10.1016/j.celrep.2016.10.023
Published in:Cell Reports
Language:English