HDAC4

Histone deacetylase 4
Catalytic domain of HDAC4 with bound inhibitor. PDB rendering based on 2vqj[1].
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2H8N​, 2O94​, 2VQJ​, 2VQM​, 2VQO​, 2VQQ​, 2VQV​, 2VQW​, 3UXG​, 3UZD​, 3V31​, 4CBT​, 4CBY​
Identifiers
Symbols	HDAC4 ; AHO3; BDMR; HA6116; HD4; HDAC-4; HDAC-A; HDACA
External IDs	OMIM: 605314 MGI: 3036234 HomoloGene: 55946 ChEMBL: 3524 GeneCards: HDAC4 Gene
EC number	3.5.1.98
Gene ontology Molecular function • RNA polymerase III transcription factor binding • core promoter binding • chromatin binding • transcription corepressor activity • histone deacetylase activity • protein binding • transcription factor binding • zinc ion binding • protein kinase binding • potassium ion binding • NAD-dependent histone deacetylase activity (H3-K14 specific) • protein deacetylase activity • activating transcription factor binding • histone deacetylase binding • sequence-specific DNA binding • transcription regulatory region DNA binding • repressing transcription factor binding Cellular component • histone deacetylase complex • nucleus • nucleoplasm • cytoplasm • cytosol • transcriptional repressor complex • Z disc • neuromuscular junction • A band • actomyosin Biological process • negative regulation of transcription from RNA polymerase II promoter • skeletal system development • osteoblast development • chromatin remodeling • transcription, DNA-templated • inflammatory response • nervous system development • positive regulation of cell proliferation • negative regulation of cell proliferation • positive regulation of lamellipodium assembly • negative regulation of myotube differentiation • regulation of cardiac muscle contraction by calcium ion signaling • response to denervation involved in regulation of muscle adaptation • cardiac muscle hypertrophy in response to stress • positive regulation of smooth muscle cell migration • histone deacetylation • B cell differentiation • positive regulation of protein sumoylation • peptidyl-lysine deacetylation • regulation of gene expression, epigenetic • B cell activation • response to drug • regulation of protein binding • negative regulation of sequence-specific DNA binding transcription factor activity • positive regulation of neuron apoptotic process • negative regulation of osteoblast differentiation • negative regulation of glycolytic process • negative regulation of transcription, DNA-templated • positive regulation of transcription, DNA-templated • positive regulation of transcription from RNA polymerase II promoter • positive regulation of smooth muscle cell proliferation • regulation of skeletal muscle fiber development • positive regulation of sequence-specific DNA binding transcription factor activity • response to interleukin-1 • histone H3 deacetylation • histone H4 deacetylation • cellular response to mechanical stimulus • cellular response to tumor necrosis factor • cellular response to parathyroid hormone stimulus • positive regulation of reactive oxygen species biosynthetic process Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	9759	208727
Ensembl	ENSG00000068024	ENSMUSG00000026313
UniProt	P56524	Q6NZM9
RefSeq (mRNA)	NM_006037	NM_207225
RefSeq (protein)	NP_006028	NP_997108
Location (UCSC)	Chr 2: 239.05 – 239.4 Mb	Chr 1: 91.93 – 92.18 Mb
PubMed search

Histone deacetylase 4, also known as HDAC4, is a protein that in humans is encoded by the HDAC4 gene.^[2][3]

Function

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 class II of the histone deacetylase/acuc/apha family. It possesses histone deacetylase activity and represses transcription when tethered to a promoter. This protein does not bind DNA directly but through transcription factors MEF2C and MEF2D. It seems to interact in a multiprotein complex with RbAp48 and HDAC3.^[4] Furthermore, HDAC4 is required for TGFbeta1-induced myofibroblastic differentiation.^[5]

Clinical significance

Studies have shown that HDAC4 regulates bone and muscle development. Harvard University researchers also concluded that it promotes healthy vision: Reduced levels of the protein led to the death of the rod photoreceptors and bipolar cells in the retinas of mice.^[6][7]

Interactions

HDAC4 has been shown to interact with:

• BCL6,^[8]
• BTG2,^[9]
• CBX5,^[10]
• GATA1,^[11]
• HDAC3,^{[2][12][13][14]}
• MAPK1,^[15]
• MAPK3,^[15]
• MEF2C,^[16][17]
• Myocyte-specific enhancer factor 2A,^[18][19]
• Nuclear receptor co-repressor 1,^[12][20]
• Nuclear receptor co-repressor 2,^[12][20]
• Testicular receptor 2,^[21][22]
• YWHAB,^[13]
• YWHAE,^[13][23] and
• Zinc finger and BTB domain-containing protein 16.^[8][24]

See also

• Histone deacetylase

References

1. Bottomley, M. J.; Lo Surdo, P.; Di Giovine, P.; Cirillo, A.; Scarpelli, R.; Ferrigno, F.; Jones, P.; Neddermann, P.; De Francesco, R.; Steinkühler, C.; Gallinari, P.; Carfí, A. (2008). "Structural and Functional Analysis of the Human HDAC4 Catalytic Domain Reveals a Regulatory Structural Zinc-binding Domain". Journal of Biological Chemistry 283 (39): 26694–26704. doi:10.1074/jbc.M803514200. PMC 3258910. PMID 18614528.
2. Grozinger CM, Hassig CA, Schreiber SL (April 1999). "Three proteins define a class of human histone deacetylases related to yeast Hda1p". Proc. Natl. Acad. Sci. U.S.A. 96 (9): 4868–73. doi:10.1073/pnas.96.9.4868. PMC 21783. PMID 10220385.
3. Fischle W, Emiliani S, Hendzel MJ, Nagase T, Nomura N, Voelter W, Verdin E (April 1999). "A new family of human histone deacetylases related to Saccharomyces cerevisiae HDA1p". J. Biol. Chem. 274 (17): 11713–20. doi:10.1074/jbc.274.17.11713. PMID 10206986.
4. "Entrez Gene: HDAC4 histone deacetylase 4".
5. Glenisson W, Castronovo V, Waltregny D (October 2007). "Histone deacetylase 4 is required for TGFbeta1-induced myofibroblastic differentiation.". Biochim Biophys Acta 1773 (10): 1572–82. doi:10.1016/j.bbamcr.2007.05.016. PMID 17610967.
6. Protein for Sight, Scientific American, 300, 3 (March 2009), p. 23
7. Chen B, Cepko CL (January 2009). "HDAC4 regulates neuronal survival in normal and diseased retinas". Science 323 (5911): 256–9. doi:10.1126/science.1166226. PMC 3339762. PMID 19131628.
8. Lemercier C, Brocard MP, Puvion-Dutilleul F, Kao HY, Albagli O, Khochbin S (June 2002). "Class II histone deacetylases are directly recruited by BCL6 transcriptional repressor". J. Biol. Chem. 277 (24): 22045–52. doi:10.1074/jbc.M201736200. PMID 11929873.
9. Farioli-Vecchioli S, Tanori M, Micheli L, Mancuso M, Leonardi L, Saran A, Ciotti MT, Ferretti E, Gulino A, Pazzaglia S, Tirone F (July 2007). "Inhibition of medulloblastoma tumorigenesis by the antiproliferative and pro-differentiative gene PC3". FASEB J. 21 (9): 2215–25. doi:10.1096/fj.06-7548com. PMID 17371797.
10. Zhang CL, McKinsey TA, Olson EN (October 2002). "Association of class II histone deacetylases with heterochromatin protein 1: potential role for histone methylation in control of muscle differentiation". Mol. Cell. Biol. 22 (20): 7302–12. doi:10.1128/mcb.22.20.7302-7312.2002. PMC 139799. PMID 12242305.
11. 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". Oncogene 22 (57): 9176–84. doi:10.1038/sj.onc.1206902. PMID 14668799.
12. Fischle 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. Cell 9 (1): 45–57. doi:10.1016/s1097-2765(01)00429-4. PMID 11804585.
13. Grozinger CM, Schreiber SL (July 2000). "Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3-dependent cellular localization". Proc. Natl. Acad. Sci. U.S.A. 97 (14): 7835–40. doi:10.1073/pnas.140199597. PMC 16631. PMID 10869435.
14. Fischle W, Dequiedt F, Fillion M, Hendzel MJ, Voelter W, Verdin E (September 2001). "Human HDAC7 histone deacetylase activity is associated with HDAC3 in vivo". J. Biol. Chem. 276 (38): 35826–35. doi:10.1074/jbc.M104935200. PMID 11466315.
15. Zhou X, Richon VM, Wang AH, Yang XJ, Rifkind RA, Marks PA (December 2000). "Histone deacetylase 4 associates with extracellular signal-regulated kinases 1 and 2, and its cellular localization is regulated by oncogenic Ras". Proc. Natl. Acad. Sci. U.S.A. 97 (26): 14329–33. doi:10.1073/pnas.250494697. PMC 18918. PMID 11114188.
16. Wang AH, Bertos NR, Vezmar M, Pelletier N, Crosato M, Heng HH, Th'ng J, Han J, Yang XJ (November 1999). "HDAC4, a human histone deacetylase related to yeast HDA1, is a transcriptional corepressor". Mol. Cell. Biol. 19 (11): 7816–27. doi:10.1128/mcb.19.11.7816. PMC 84849. PMID 10523670.
17. Wang AH, Yang XJ (September 2001). "Histone deacetylase 4 possesses intrinsic nuclear import and export signals". Mol. Cell. Biol. 21 (17): 5992–6005. doi:10.1128/mcb.21.17.5992-6005.2001. PMC 87317. PMID 11486037.
18. Miska EA, Karlsson C, Langley E, Nielsen SJ, Pines J, Kouzarides T (September 1999). "HDAC4 deacetylase associates with and represses the MEF2 transcription factor". EMBO J. 18 (18): 5099–107. doi:10.1093/emboj/18.18.5099. PMC 1171580. PMID 10487761.
19. Lemercier C, Verdel A, Galloo B, Curtet S, Brocard MP, Khochbin S (May 2000). "mHDA1/HDAC5 histone deacetylase interacts with and represses MEF2A transcriptional activity". J. Biol. Chem. 275 (20): 15594–9. doi:10.1074/jbc.M908437199. PMID 10748098.
20. Huang EY, Zhang J, Miska EA, Guenther MG, Kouzarides T, Lazar MA (January 2000). "Nuclear receptor corepressors partner with class II histone deacetylases in a Sin3-independent repression pathway". Genes Dev. 14 (1): 45–54. PMC 316335. PMID 10640275.
21. Franco PJ, Li G, Wei LN (August 2003). "Interaction of nuclear receptor zinc finger DNA binding domains with histone deacetylase". Mol. Cell. Endocrinol. 206 (1-2): 1–12. doi:10.1016/s0303-7207(03)00254-5. PMID 12943985.
22. 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. PMID 11463856.
23. Miska EA, Langley E, Wolf D, Karlsson C, Pines J, Kouzarides T (August 2001). "Differential localization of HDAC4 orchestrates muscle differentiation". Nucleic Acids Res. 29 (16): 3439–47. doi:10.1093/nar/29.16.3439. PMC 55849. PMID 11504882.
24. Chauchereau A, Mathieu M, de Saintignon J, Ferreira R, Pritchard LL, Mishal Z, Dejean A, Harel-Bellan A (November 2004). "HDAC4 mediates transcriptional repression by the acute promyelocytic leukaemia-associated protein PLZF". Oncogene 23 (54): 8777–84. doi:10.1038/sj.onc.1208128. PMID 15467736.

Further reading

• Pazin MJ, Kadonaga JT (1997). "What's up and down with histone deacetylation and transcription?". Cell 89 (3): 325–8. doi:10.1016/S0092-8674(00)80211-1. PMID 9150131.
• Verdin E, Dequiedt F, Kasler HG (2003). "Class II histone deacetylases: versatile regulators.". Trends Genet. 19 (5): 286–93. doi:10.1016/S0168-9525(03)00073-8. PMID 12711221.
• Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA (1996). "A "double adaptor" method for improved shotgun library construction.". Anal. Biochem. 236 (1): 107–13. doi:10.1006/abio.1996.0138. PMID 8619474.
• Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA (1997). "Large-scale concatenation cDNA sequencing.". Genome Res. 7 (4): 353–8. doi:10.1101/gr.7.4.353. PMC 139146. PMID 9110174.
• Wolffe AP (1997). "Transcriptional control. Sinful repression.". Nature 387 (6628): 16–7. doi:10.1038/387016a0. PMID 9139815.
• Ohara O, Nagase T, Ishikawa K, Nakajima D, Ohira M, Seki N, Nomura N (1997). "Construction and characterization of human brain cDNA libraries suitable for analysis of cDNA clones encoding relatively large proteins.". DNA Res. 4 (1): 53–9. doi:10.1093/dnares/4.1.53. PMID 9179496.
• Fischle W, Emiliani S, Hendzel MJ, Nagase T, Nomura N, Voelter W, Verdin E (1999). "A new family of human histone deacetylases related to Saccharomyces cerevisiae HDA1p.". J. Biol. Chem. 274 (17): 11713–20. doi:10.1074/jbc.274.17.11713. PMID 10206986.
• Grozinger CM, Hassig CA, Schreiber SL (1999). "Three proteins define a class of human histone deacetylases related to yeast Hda1p.". Proc. Natl. Acad. Sci. U.S.A. 96 (9): 4868–73. doi:10.1073/pnas.96.9.4868. PMC 21783. PMID 10220385.
• Miska EA, Karlsson C, Langley E, Nielsen SJ, Pines J, Kouzarides T (1999). "HDAC4 deacetylase associates with and represses the MEF2 transcription factor.". EMBO J. 18 (18): 5099–107. doi:10.1093/emboj/18.18.5099. PMC 1171580. PMID 10487761.
• Wang AH, Bertos NR, Vezmar M, Pelletier N, Crosato M, Heng HH, Th'ng J, Han J, Yang XJ (1999). "HDAC4, a human histone deacetylase related to yeast HDA1, is a transcriptional corepressor.". Mol. Cell. Biol. 19 (11): 7816–27. doi:10.1128/mcb.19.11.7816. PMC 84849. PMID 10523670.
• Youn HD, Grozinger CM, Liu JO (2000). "Calcium regulates transcriptional repression of myocyte enhancer factor 2 by histone deacetylase 4.". J. Biol. Chem. 275 (29): 22563–7. doi:10.1074/jbc.C000304200. PMID 10825153.
• Grozinger CM, Schreiber SL (2000). "Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3-dependent cellular localization.". Proc. Natl. Acad. Sci. U.S.A. 97 (14): 7835–40. doi:10.1073/pnas.140199597. PMC 16631. PMID 10869435.
• Huynh KD, Fischle W, Verdin E, Bardwell VJ (2000). "BCoR, a novel corepressor involved in BCL-6 repression.". Genes Dev. 14 (14): 1810–23. doi:10.1101/gad.14.14.1810. PMC 316791. PMID 10898795.
• Li J, Wang J, Wang J, Nawaz Z, Liu JM, Qin J, Wong J (2000). "Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3.". EMBO J. 19 (16): 4342–50. doi:10.1093/emboj/19.16.4342. PMC 302030. PMID 10944117.
• Wang AH, Kruhlak MJ, Wu J, Bertos NR, Vezmar M, Posner BI, Bazett-Jones DP, Yang XJ (2000). "Regulation of histone deacetylase 4 by binding of 14-3-3 proteins.". Mol. Cell. Biol. 20 (18): 6904–12. doi:10.1128/MCB.20.18.6904-6912.2000. PMC 88766. PMID 10958686.
• Zhang CL, McKinsey TA, Lu JR, Olson EN (2001). "Association of COOH-terminal-binding protein (CtBP) and MEF2-interacting transcription repressor (MITR) contributes to transcriptional repression of the MEF2 transcription factor.". J. Biol. Chem. 276 (1): 35–9. doi:10.1074/jbc.M007364200. PMID 11022042.
• McKinsey TA, Zhang CL, Lu J, Olson EN (2000). "Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation.". Nature 408 (6808): 106–11. doi:10.1038/35040593. PMID 11081517.
• Zhou X, Richon VM, Wang AH, Yang XJ, Rifkind RA, Marks PA (2001). "Histone deacetylase 4 associates with extracellular signal-regulated kinases 1 and 2, and its cellular localization is regulated by oncogenic Ras.". Proc. Natl. Acad. Sci. U.S.A. 97 (26): 14329–33. doi:10.1073/pnas.250494697. PMC 18918. PMID 11114188.
• McKinsey TA, Zhang CL, Olson EN (2001). "Activation of the myocyte enhancer factor-2 transcription factor by calcium/calmodulin-dependent protein kinase-stimulated binding of 14-3-3 to histone deacetylase 5.". Proc. Natl. Acad. Sci. U.S.A. 97 (26): 14400–5. doi:10.1073/pnas.260501497. PMC 18930. PMID 11114197.

External links

• HDAC4 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.