Histone deacetylase 3 (HDAC3) is the enzymatic component of transcriptional repression complexes recruited by the nuclear hormone receptors. Inactivation of HDAC3 in cancer cell lines triggered apoptosis, and removal of Hdac3 in the germ-line of mice caused embryonic lethality. HDAC3 binding sites within the hematopoietic transcription factor RUNX1 were required for RUNX1-mediated gene repression. Therefore, Hdac3 was conditionally deleted in the postnatal mouse hematopoietic system (Mx:Hdac3). The Mx:Hdac3 mice had increased numbers of double positive (c-Kit+/Sca+) hematopoietic stem cells, yet these progenitor cells not able to survive or proliferate in a colony forming assay. Mx:Hdac3 mice also developed reversible liver hypertrophy, so Hdac3 was constitutively deleted in the liver (Alb:Hdac3). The Alb:Hdac3 mice also developed hepatomegaly, which was the result of hepatocyte hypertrophy. These morphological changes coincided with significant imbalances between carbohydrate and lipid metabolism. Liver-specific deletion of Hdac3 triggered changes in gene expression consistent with inactivation of repression mediated by nuclear hormone receptors. Loss of Hdac3 also increased the levels of Pparã2, and treatment of these mice with a PPARã antagonist partially reversed the lipid accumulation in the liver. In addition, gene expression analysis identified mammalian target of rapamycin (mTOR) signaling as being activated after deletion of Hdac3, and inhibition by rapamycin affected the accumulation of neutral lipids in the Hdac3-null livers. As the Alb:Hdac3 mice aged, accumulation of endogenous DNA damage and disrupted metabolism most likely contributed to the development of non-alcoholic steatohepatitis (NASH)-like symptoms, and ultimately, hepatocellular carcinoma. Thus, Hdac3 plays a critical role in mediating normal cellular homeostasis in both the adult hematopoietic system and liver, as demonstrated by the Mx:Hdac3 and Alb:Hdac3 conditional deletion models.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-05222008-164304 |
| Date | 30 May 2008 |
| Creators | Knutson, Sarah Kathleen |
| Contributors | Professor Scott Hiebert, Professor Jennifer Pietenpol, Professor Bruce Carter, Professor Andrew Link, Professor Zu-Wen Sun |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-05222008-164304/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
Page generated in 0.0075 seconds