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

Dae Hwan Kim, Janghyun Kim, Ji Sun Kwon, Jaspreet Sandhu, Peter Tontonoz, Soo-Kyung Lee, Seunghee Lee, Jae Lee

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1671-1682
Number of pages12
JournalCell Reports
Volume17
Issue number6
DOIs
StatePublished - Nov 1 2016

Fingerprint

Overnutrition
Genes
Liver
Lysine
Methylation
Methyltransferases
Histones
Chromatin
Transcription Factors
Phosphotransferases
Fatty Liver
Regulator Genes
Transcriptional Activation
Pharmaceutical Preparations
histone methyltransferase

Keywords

  • ABL1
  • fatty liver
  • imatinib
  • KMT2D
  • MLL4
  • NAFLD
  • PPAR gamma
  • UTX

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Critical Roles of the Histone Methyltransferase MLL4/KMT2D in Murine Hepatic Steatosis Directed by ABL1 and PPARγ2. / Kim, Dae Hwan; Kim, Janghyun; Kwon, Ji Sun; Sandhu, Jaspreet; Tontonoz, Peter; Lee, Soo-Kyung; Lee, Seunghee; Lee, Jae.

In: Cell Reports, Vol. 17, No. 6, 01.11.2016, p. 1671-1682.

Research output: Contribution to journalArticle

Kim, Dae Hwan ; Kim, Janghyun ; Kwon, Ji Sun ; Sandhu, Jaspreet ; Tontonoz, Peter ; Lee, Soo-Kyung ; Lee, Seunghee ; Lee, Jae. / Critical Roles of the Histone Methyltransferase MLL4/KMT2D in Murine Hepatic Steatosis Directed by ABL1 and PPARγ2. In: Cell Reports. 2016 ; Vol. 17, No. 6. pp. 1671-1682.
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