title: TRIM24 suppresses development of spontaneous hepatic lipid accumulation and hepatocellular carcinoma in mice.
abstract: OBJECTIVE
  Aberrantly high expression of TRIM24 occurs in human cancers, including hepatocellular carcinoma. In contrast, TRIM24 in the mouse is reportedly a liver-specific tumour suppressor. To address this dichotomy and to uncover direct regulatory functions of TRIM24 in vivo, we developed a new mouse model that lacks expression of all Trim24 isoforms, as the previous model expressed normal levels of Trim24 lacking only exon 4.
  
  
  METHODS
  To produce germline-deleted Trim24(dlE1) mice, deletion of the promoter and exon 1 of Trim24 was induced in Trim24(LoxP) mice by crossing with a zona pellucida 3-Cre line for global deletion. Liver-specific deletion (Trim24(hep)) was achieved by crossing with an albumin-Cre line. Phenotypic analyses were complemented by protein, gene-specific and global RNA expression analyses and quantitative chromatin immunoprecipitation.
  
  
  RESULTS
  Global loss of Trim24 disrupted hepatic homeostasis in 100% of mice with highly significant, decreased expression of oxidation/reduction, steroid, fatty acid, and lipid metabolism genes, as well as increased expression of genes involved in unfolded protein response, endoplasmic reticulum stress and cell cycle pathways. Trim24(dlE1/dlE1) mice have markedly depleted visceral fat and, like Trim24(hep/hep) mice, spontaneously develop hepatic lipid-filled lesions, steatosis, hepatic injury, fibrosis and hepatocellular carcinoma.
  
  
  CONCLUSIONS
  TRIM24, an epigenetic co-regulator of transcription, directly and indirectly represses hepatic lipid accumulation, inflammation, fibrosis and damage in the murine liver. Complete loss of Trim24 offers a model of human non-alcoholic fatty liver disease, steatosis, fibrosis and development of hepatocellular carcinoma in the absence of high-fat diet or obesity.
authors.affiliation: Department of Biochemistry and Molecular Biology, UT MD Anderson Cancer Center, Houston, TX, USA; Center for Stem Cell and Developmental Biology, UT MD Anderson Cancer Center, Houston, TX, USA; Center for Cancer Epigenetics, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Shiming
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Department of Biochemistry and Molecular Biology, UT MD Anderson Cancer Center, Houston, TX, USA; Center for Stem Cell and Developmental Biology, UT MD Anderson Cancer Center, Houston, TX, USA; Center for Cancer Epigenetics, UT MD Anderson Cancer Center, Houston, TX, USA; Graduate Program in Genes and Development, University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
authors.forename: Lindsey Cauthen
authors.initials: LC
authors.lastname: Minter
authors.affiliation: Department of Biochemistry and Molecular Biology, UT MD Anderson Cancer Center, Houston, TX, USA; Center for Stem Cell and Developmental Biology, UT MD Anderson Cancer Center, Houston, TX, USA; Center for Cancer Epigenetics, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Sabrina A
authors.initials: SA
authors.lastname: Stratton
authors.affiliation: Department of Genetics, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Peirong
authors.initials: P
authors.lastname: Yang
authors.affiliation: Department of Genetics, UT MD Anderson Cancer Center, Houston, TX, USA; Graduate Program in Genes and Development, University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
authors.forename: Hussein A
authors.initials: HA
authors.lastname: Abbas
authors.affiliation: Department of Biochemistry and Molecular Biology, UT MD Anderson Cancer Center, Houston, TX, USA; Center for Stem Cell and Developmental Biology, UT MD Anderson Cancer Center, Houston, TX, USA; Center for Cancer Epigenetics, UT MD Anderson Cancer Center, Houston, TX, USA; Graduate Program in Genes and Development, University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
authors.forename: Zeynep Coban
authors.initials: ZC
authors.lastname: Akdemir
authors.affiliation: Department of Genetics, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Vinod
authors.initials: V
authors.lastname: Pant
authors.affiliation: Department of Leukemia, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Post
authors.affiliation: Department of Veterinary Medicine and Surgery, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Mihai
authors.initials: M
authors.lastname: Gagea
authors.affiliation: Isis Pharmaceuticals, Carlsbad, CA, USA.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Lee
authors.affiliation: Department of Genetics, UT MD Anderson Cancer Center, Houston, TX, USA; Graduate Program in Genes and Development, University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
authors.forename: Guillermina
authors.initials: G
authors.lastname: Lozano
authors.affiliation: Department of Biochemistry and Molecular Biology, UT MD Anderson Cancer Center, Houston, TX, USA; Center for Stem Cell and Developmental Biology, UT MD Anderson Cancer Center, Houston, TX, USA; Center for Cancer Epigenetics, UT MD Anderson Cancer Center, Houston, TX, USA; Graduate Program in Genes and Development, University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA. Electronic address: mbarton@mdanderson.org.
authors.forename: Michelle Craig
authors.initials: MC
authors.lastname: Barton
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008055:Lipids / Q000032:analysis*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012334:RNA, Neoplasm / Q000235:genetics*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D008055:Lipids; D009687:Nuclear Proteins; D012334:RNA, Neoplasm; D014157:Transcription Factors; C093517:transcriptional intermediary factor 1
keywords: HCC; Hepatic lesions; Histone reader; NAFLD; NASH; Steatosis