Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromosome structure and affects transcription factor access to DNA. The protein encoded by this gene belongs to the histone deacetylase/acuc/apha family. It has histone deacetylase activity and represses transcription when tethered to a promoter. It may participate in the regulation of transcription through its binding with the zinc-finger transcription factor YY1. This protein can also down-regulate p53 function and thus modulate cell growth and apoptosis. This gene is regarded as a potential tumor suppressor gene.
This enzyme is involved in the coordination of commensal-bacteria-dependent intestinal homeostasis when expressed in intestinal epithelial cells.
Histone deacetylases can be regulated by endogenous factors, dietary components, synthetic inhibitors and bacteria-derived signals. Studies in mice with a specific deletion of HDAC3 in intestinal epithelial cells (IECs) show a deregulated IEC’s gene expression. In these deletion-mutant mice, loss of Paneth cells, impaired IEC function and alterations in intestinal composition of commensal bacteria were observed. These negative effects were not observed in germ-free mice, indicating that the effects of the deletion are only seen in the presence of intestinal microbial colonization. But the negative effects of HDAC3 deletion are not due to the presence of an altered microbiota because normal germ-free mice colonized with the altered microbiota did not show the negative effects seen in deletion mutants.
Although the precise mechanism and the specific signals are not known it is clear that HDAC3 interacts with derived signals of commensal bacteria of the gut microbiota. These interactions are responsible of calibrating epithelial cells responses necessary to establish a normal relationship between the host and the commensal as well as to maintain intestinal homeostasis.
Twenty six tests were carried out on mutant mice and two significant abnormalities were observed. No homozygousmutant embryos were identified during gestation, and in a separate study none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no significant abnormalities were observed in these animals.
^Dangond F, Hafler DA, Tong JK, Randall J, Kojima R, Utku N, Gullans SR (March 1998). "Differential display cloning of a novel human histone deacetylase (HDAC3) cDNA from PHA-activated immune cells". Biochem Biophys Res Commun242 (3): 648–52. doi:10.1006/bbrc.1997.8033. PMID9464271.
^Petre-Draviam CE, Williams EB, Burd CJ, Gladden A, Moghadam H, Meller J, Diehl JA, Knudsen KE (January 2005). "A central domain of cyclin D1 mediates nuclear receptor corepressor activity". Oncogene24 (3): 431–44. doi:10.1038/sj.onc.1208200. PMID15558026.
^Lin HM, Zhao L, Cheng SY (August 2002). "Cyclin D1 Is a Ligand-independent Co-repressor for Thyroid Hormone Receptors". J. Biol. Chem.277 (32): 28733–41. doi:10.1074/jbc.M203380200. PMID12048199.
^Watamoto K, Towatari M, Ozawa Y, Miyata Y, Okamoto M, Abe A, Naoe T, Saito H (December 2003). "Altered interaction of HDAC5 with GATA-1 during MEL cell differentiation". Oncogene22 (57): 9176–84. doi:10.1038/sj.onc.1206902. PMID14668799.
^Ozawa Y, Towatari M, Tsuzuki S, Hayakawa F, Maeda T, Miyata Y, Tanimoto M, Saito H (October 2001). "Histone deacetylase 3 associates with and represses the transcription factor GATA-2". Blood98 (7): 2116–23. doi:10.1182/blood.V98.7.2116. PMID11567998.
^ abcdZhang J, Kalkum M, Chait BT, Roeder RG (March 2002). "The N-CoR-HDAC3 nuclear receptor corepressor complex inhibits the JNK pathway through the integral subunit GPS2". Mol. Cell9 (3): 611–23. doi:10.1016/S1097-2765(02)00468-9. PMID11931768.
^Wen YD, Cress WD, Roy AL, Seto E (January 2003). "Histone deacetylase 3 binds to and regulates the multifunctional transcription factor TFII-I". J. Biol. Chem.278 (3): 1841–7. doi:10.1074/jbc.M206528200. PMID12393887.
^ abcdFischle W, Dequiedt F, Hendzel MJ, Guenther MG, Lazar MA, Voelter W, Verdin E (January 2002). "Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR". Mol. Cell9 (1): 45–57. doi:10.1016/S1097-2765(01)00429-4. PMID11804585.
^Baek SH, Ohgi KA, Rose DW, Koo EH, Glass CK, Rosenfeld MG (July 2002). "Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-kappaB and beta-amyloid precursor protein". Cell110 (1): 55–67. doi:10.1016/S0092-8674(02)00809-7. PMID12150997.
^Mahlknecht U, Will J, Varin A, Hoelzer D, Herbein G (September 2004). "Histone deacetylase 3, a class I histone deacetylase, suppresses MAPK11-mediated activating transcription factor-2 activation and represses TNF gene expression". J. Immunol.173 (6): 3979–90. doi:10.4049/jimmunol.173.6.3979. PMID15356147.
^ abcYoon HG, Chan DW, Reynolds AB, Qin J, Wong J (September 2003). "N-CoR mediates DNA methylation-dependent repression through a methyl CpG binding protein Kaiso". Mol. Cell12 (3): 723–34. doi:10.1016/j.molcel.2003.08.008. PMID14527417.
^Li G, Franco PJ, Wei LN (October 2003). "Identification of histone deacetylase-3 domains that interact with the orphan nuclear receptor TR2". Biochem. Biophys. Res. Commun.310 (2): 384–90. doi:10.1016/j.bbrc.2003.08.145. PMID14521922.
^Franco PJ, Farooqui M, Seto E, Wei LN (August 2001). "The orphan nuclear receptor TR2 interacts directly with both class I and class II histone deacetylases". Mol. Endocrinol.15 (8): 1318–28. doi:10.1210/mend.15.8.0682. PMID11463856.
^Tan F, Lu L, Cai Y, Wang J, Xie Y, Wang L, Gong Y, Xu BE, Wu J, Luo Y, Qiang B, Yuan J, Sun X, Peng X (July 2008). "Proteomic analysis of ubiquitinated proteins in normal hepatocyte cell line Chang liver cells". Proteomics8 (14): 2885–96. doi:10.1002/pmic.200700887. PMID18655026.
^Yang WM, Yao YL, Sun JM, Davie JR, Seto E (October 1997). "Isolation and characterization of cDNAs corresponding to an additional member of the human histone deacetylase gene family". J. Biol. Chem.272 (44): 28001–7. doi:10.1074/jbc.272.44.28001. PMID9346952.