Chromatin Regulator | Alias |
| HDAC3 | HD3; RPD3; RPD3-2 |
External Links: | Wiki GeneCards NCBI UniProt |
Related histone modifications: | H3K4ac;H3K14ac |
Introduction | |
| Full Name: Histone deacetylase 3
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HDAC3 is a deacetylase belonging to the Class I HDACs, and corepressors such as NCoR (nuclear receptor corepressor) and SMRT (silencing mediator of retinoic and thyroid receptors) form part of the HDAC3 complex, acting as activating cofactors. HDAC3 is involved in differentiation, circadian metabolism, cardiac development, macrophage alternative activation, and maintaining proper mitochondrial function (1-7).
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Function and Interaction | |
| HDAC3 is recruited by nuclear hormone receptors, leading to transcriptional control without hormones, indicating that it is essential for the normal physiological function of many nuclear hormone receptors (8). Suppression of HDAC3 in mouse embryonic fibroblasts (MEFs) results in a delay in S phase progression and related DNA damage. Moreover, an HDAC3 knockout in the germ line leads to early embryonic lethality. Specific deletion of HDAC3 in the liver can result in the disorganization of normal metabolic pathways (8-9). HDAC3 has been found to associate with Runx2, thus modulating osteoblast differentiation and bone formation (10). HDAC3 is thought to be an important regulator of endothelial progenitor cell (EPC) differentiation through the Flk-1-PI3K-Akt-HDAC3-p53-p21 pathway (11). HDAC3 is a transcriptional suppressor that acts as a key regulator of cardiac development, and it can affect cell-cycle progression, cardiac myocyte proliferation, and cardiac energy metabolism and function (1,12-13).
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Disease Association | |
| HDAC3 has been shown to be recruited by Rev-erbα, a circadian nuclear receptor, to genes associated with modulation of lipid metabolism, and its deletion can result in hepatic steatosis (14). Furthermore, HDAC3 interacts with Myc and is recruited to the miR-15a/16-1 promoter region through this factor, thus repressing miR-15a/16-1 transcription in mantle cell lymphoma (MCL) (15). HDAC3 is also a candidate target for the treatment of pediatric B-cell acute lymphocytic leukemia and acute myeloid leukemia (16-19).
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ChIP-Seq data
ChIP-Seq data of related histone modifications
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References | |
1. Sun, Z., Singh, N., Mullican, S.E., Everett, L.J., Li, L., Yuan, L.J., Liu, X., Epstein, J.A. and Lazar, M.A. (2011) Diet-induced Lethality Due to Deletion of the Hdac3 Gene in Heart and Skeletal Muscle. J Biol Chem, 286, 33301-33309.
2. Alenghat, T., Meyers, K., Mullican, S.E., Leitner, K., Adeniji-Adele, A., Avila, J., Bucan, M., Ahima, R.S., Kaestner, K.H. and Lazar, M.A. (2008) Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology. Nature, 456, 997-U988.
3. Mullican, S.E., Gaddis, C.A., Alenghat, T., Nair, M.G., Giacomin, P.R., Everett, L.J., Feng, D., Steger, D.J., Schug, J., Artis, D. et al. (2011) Histone deacetylase 3 is an epigenomic brake in macrophage alternative activation. Genes Dev, 25, 2480-2488.
4. Guenther, M.G., Lane, W.S., Fischle, W., Verdin, E., Lazar, M.A. and Shiekhattar, R. (2000) A core SMRT corepressor complex containing HDAC3 and TBL1, a WD40-repeat protein linked to deafness. Genes Dev, 14, 1048-1057.
5. Li, J.W., Wang, J., Wang, J.X., Nawaz, Z., Liu, J.M., Qin, J. and Wong, J.M. (2000) Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3. Embo Journal, 19, 4342-4350.
6. Wen, Y.D., Perissi, V., Staszewski, L.M., Yang, W.M., Krones, A., Glass, C.K., Rosenfeld, M.G. and Seto, E. (2000) The histone deacetylase-3 complex contains nuclear receptor corepressors. P Natl Acad Sci USA, 97, 7202-7207.
7. Guenther, M.G., Barak, O. and Lazar, M.A. (2001) The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3. Mol Cell Biol, 21, 6091-6101.
8. Knutson, S.K., Chyla, B.J., Amann, J.M., Bhaskara, S., Huppert, S.S. and Hiebert, S.W. (2008) Liver-specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networks. Embo Journal, 27, 1017-1028.
9. Bhaskara, S., Chyla, B.J., Amann, J.M., Knutson, S.K., Cortez, D., Sun, Z.W. and Hiebert, S.W. (2008) Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control. Mol Cell, 30, 61-72.
10. Schroeder, T.M., Kahler, R.A., Li, X.D. and Westendorf, J.J. (2004) Histone deacetylase 3 interacts with Runx2 to repress the osteocalcin promoter and regulate osteoblast differentiation. J Biol Chem, 279, 41998-42007.
11. Zeng, L.F., Xiao, Q.Z., Margariti, A., Zhang, Z.Y., Zampetaki, A., Patel, S., Capogrossi, M.C., Hu, Y.H. and Xu, Q.B. (2006) HDAC3 is crucial in shear- and VEGF-induced stem cell differentiation toward endothelial cells. J Cell Biol, 174, 1059-1069.
12. Montgomery, R.L., Potthoff, M.J., Haberland, M., Qi, X.X., Matsuzaki, S., Humphries, K.M., Richardson, J.A., Bassel-Duby, R. and Olson, E.N. (2008) Maintenance of cardiac energy by histone deacetylase 3 metabolism in mice. J Clin Invest, 118, 3588-3597.
13. Trivedi, C.M., Lu, M.M., Wang, Q.H. and Epstein, J.A. (2008) Transgenic overexpression of Hdac3 in the heart produces increased postnatal cardiac myocyte proliferation but does not induce hypertrophy. J Biol Chem, 283, 26484-26489.
14. Feng, D., Liu, T., Sun, Z., Bugge, A., Mullican, S.E., Alenghat, T., Liu, X.S. and Lazar, M.A. (2011) A Circadian Rhythm Orchestrated by Histone Deacetylase 3 Controls Hepatic Lipid Metabolism. Science, 331, 1315-1319.
15. Zhang, X., Chen, X., Lin, J., Lwin, T., Wright, G., Moscinski, L.C., Dalton, W.S., Seto, E., Wright, K., Sotomayor, E. et al. (2012) Myc represses miR-15a/miR-16-1 expression through recruitment of HDAC3 in mantle cell and other non-Hodgkin B-cell lymphomas. Oncogene, 31, 3002-3008.
16. Guidez, F., Petrie, K., Ford, A.M., Lu, H.F., Bennett, C.A., MacGregor, A., Hannemann, J., Ito, Y., Ghysdael, J., Greaves, M. et al. (2000) Recruitment of the nuclear receptor corepressor N-CoR by the TEL moiety of the childhood leukemia-associated TEL-AML1 oncoprotein. Blood, 96, 2557-2561.
17. Amann, J.M., Nip, J., Strom, D.K., Lutterbach, B., Harada, H., Lenny, N., Downing, J.R., Meyers, S. and Hiebert, S.W. (2001) ETO, a target of t(8;21) in acute leukemia, makes distinct contacts with multiple histone deacetylases and binds mSin3A through its oligomerization domain. Mol Cell Biol, 21, 6470-6483.
18. Wang, L.L. and Hiebert, S.W. (2001) TEL contacts multiple co-repressors and specifically associates with histone deacetylase-3. Oncogene, 20, 3716-3725.
19. Chakrabarti, S.R. and Nucifora, G. (1999) The leukemia-associated gene TEL encodes a transcription repressor which associates with SMRT and mSin3A. Biochem Bioph Res Co, 264, 871-877.
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