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| Status |
Public on Mar 23, 2015 |
| Title |
TRIM24 suppresses development of spontaneous hepatic lipid accumulation and hepatocellular carcinoma in mice |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Purpose: berrantly high expression of TRIM24 occurs in human cancers, including hepatocellular carcinoma. In contrast, TRIM24 in the mouse is reportedly a liver-specific tumor suppressor. To address this dichotomy and 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 expresses normal levels of Trim24 lacking only exon 4.
Methods: To produce germline-deleted Trim24dlE1 mice, deletion of the promoter and exon 1 of Trim24 was induced in Trim24LoxP mice by crossing with a zona pellucida 3-Cre line for global deletion. Liver-specific deletion (Trim24hep) 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 in unfolded protein, endoplasmic reticulum stress and cell cycle pathways. Trim24dlE1/dlE1 mice have markedly depleted visceral fat and, like Trim24hep/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 nonalcoholic fatty liver disease, steatosis, fibrosis and development of hepatocellular carcinoma in the absence of high-fat diet or obesity.
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| Overall design |
mRNA profiles of 8 weeks wild type (WT) and Trim24-/- mice were generated by deep sequencing, in triplicate, using Illumina HiSeq 2000
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| Contributor(s) |
Coban Akdemir ZH |
| Citation(s) |
25281858 |
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| Submission date |
Sep 04, 2014 |
| Last update date |
May 15, 2019 |
| Contact name |
Michelle C. Barton |
| E-mail(s) |
mbarton@mdanderson.org
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| Organization name |
The University of Texas MD Anderson Cancer Center
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| Department |
Department of Epigenetics and Molecular Carcinogenesis,
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| Street address |
6767 Bertner St. Unit Number: 1000 Room Number: S9.8116B
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| City |
HOUSTON |
| State/province |
TEXAS |
| ZIP/Postal code |
77030 |
| Country |
USA |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA260282 |
| SRA |
SRP046242 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE61117_RAW.tar |
520.0 Kb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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