HDAC4

HDAC4
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, 5A2S
Identifiers
Aliases	HDAC4, AHO3, BDMR, HA6116, HD4, HDAC-4, HDAC-A, HDACA, histone deacetylase 4
External IDs	MGI: 3036234 HomoloGene: 55946 GeneCards: HDAC4
Gene ontology
Molecular function	• NAD-dependent histone deacetylase activity (H3-K14 specific); • sequence-specific DNA binding; • DNA binding; • core promoter binding; • transcription corepressor activity; • histone deacetylase activity; • zinc ion binding; • transcription factor binding; • histone deacetylase binding; • potassium ion binding; • chromatin binding; • activating transcription factor binding; • metal ion binding; • protein binding; • RNA polymerase III transcription factor binding; • transcription regulatory region DNA binding; • repressing transcription factor binding; • protein kinase binding; • hydrolase activity; • protein deacetylase activity;
Cellular component	• cytoplasm; • histone deacetylase complex; • neuromuscular junction; • transcriptional repressor complex; • sarcomere; • protein complex; • Z disc; • A band; • actomyosin; • nucleus; • cytosol; • nucleoplasm;
Biological process	• positive regulation of reactive oxygen species biosynthetic process; • histone H3 deacetylation; • skeletal system development; • chromatin remodeling; • peptidyl-lysine deacetylation; • regulation of cardiac muscle contraction by calcium ion signaling; • negative regulation of glycolytic process; • response to interleukin-1; • regulation of transcription, DNA-templated; • regulation of gene expression, epigenetic; • cellular response to tumor necrosis factor; • positive regulation of sequence-specific DNA binding transcription factor activity; • negative regulation of transcription from RNA polymerase II promoter; • positive regulation of protein sumoylation; • negative regulation of sequence-specific DNA binding transcription factor activity; • negative regulation of osteoblast differentiation; • transcription, DNA-templated; • nervous system development; • regulation of striated muscle cell differentiation; • positive regulation of transcription, DNA-templated; • positive regulation of smooth muscle cell migration; • B cell activation; • histone H4 deacetylation; • cellular response to mechanical stimulus; • positive regulation of neuron apoptotic process; • cardiac muscle hypertrophy in response to stress; • positive regulation of cell proliferation; • negative regulation of myotube differentiation; • response to denervation involved in regulation of muscle adaptation; • regulation of skeletal muscle fiber development; • osteoblast development; • B cell differentiation; • cellular response to parathyroid hormone stimulus; • inflammatory response; • positive regulation of lamellipodium assembly; • regulation of protein binding; • negative regulation of transcription, DNA-templated; • histone deacetylation; • response to drug; • positive regulation of transcription from RNA polymerase II promoter; • negative regulation of cell proliferation; • positive regulation of smooth muscle cell proliferation; • covalent chromatin modification; • chromatin organization; • negative regulation of pri-miRNA transcription from RNA polymerase II promoter; • protein deacetylation;
	Sources:Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	9759
	208727
	ENSG00000068024
	ENSMUSG00000026313
	P56524
	Q6NZM9
	NM_006037
	NM_207225
	NP_006028
	NP_997108
	Wikidata
View/Edit Human	View/Edit Mouse

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

Function[edit]

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.^[5] Furthermore, HDAC4 is required for TGFbeta1-induced myofibroblastic differentiation.^[6]

Clinical significance[edit]

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.^[7]^[8]

Interactions[edit]

HDAC4 has been shown to interact with:

References[edit]

^ "Human PubMed Reference:".
^ "Mouse PubMed Reference:".
^ ^a ^b 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. PMC 21783 . PMID 10220385. doi:10.1073/pnas.96.9.4868.
^ 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. PMID 10206986. doi:10.1074/jbc.274.17.11713.
^ "Entrez Gene: HDAC4 histone deacetylase 4".
^ 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. PMID 17610967. doi:10.1016/j.bbamcr.2007.05.016.
^ Protein for Sight, Scientific American, 300, 3 (March 2009), p. 23
^ Chen B, Cepko CL (January 2009). "HDAC4 regulates neuronal survival in normal and diseased retinas". Science. 323 (5911): 256–9. PMC 3339762 . PMID 19131628. doi:10.1126/science.1166226.
^ ^a ^b 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. PMID 11929873. doi:10.1074/jbc.M201736200.
^ 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. PMID 17371797. doi:10.1096/fj.06-7548com.
^ Micheli L, D'Andrea G, Leonardi L & Tirone F (2017). "HDAC1, HDAC4, and HDAC9 Bind to PC3/Tis21/Btg2 and Are Required for Its Inhibition of Cell Cycle Progression and Cyclin D1 Expression". Journal of cellular physiology. 232 (7): 1696–1707. PMID 27333946. doi:10.1002/jcp.25467.
^ 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. PMC 139799 . PMID 12242305. doi:10.1128/mcb.22.20.7302-7312.2002.
^ 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. PMID 14668799. doi:10.1038/sj.onc.1206902.
^ ^a ^b ^c 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. PMID 11804585. doi:10.1016/s1097-2765(01)00429-4.
^ ^a ^b ^c 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. PMC 16631 . PMID 10869435. doi:10.1073/pnas.140199597.
^ 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. PMID 11466315. doi:10.1074/jbc.M104935200.
^ ^a ^b 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. PMC 18918 . PMID 11114188. doi:10.1073/pnas.250494697.
^ 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. PMC 84849 . PMID 10523670. doi:10.1128/mcb.19.11.7816.
^ Wang AH, Yang XJ (September 2001). "Histone deacetylase 4 possesses intrinsic nuclear import and export signals". Mol. Cell. Biol. 21 (17): 5992–6005. PMC 87317 . PMID 11486037. doi:10.1128/mcb.21.17.5992-6005.2001.
^ 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. PMC 1171580 . PMID 10487761. doi:10.1093/emboj/18.18.5099.
^ 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. PMID 10748098. doi:10.1074/jbc.M908437199.
^ ^a ^b 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.
^ 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. PMID 12943985. doi:10.1016/s0303-7207(03)00254-5.
^ 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. PMID 11463856. doi:10.1210/mend.15.8.0682.
^ 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. PMC 55849 . PMID 11504882. doi:10.1093/nar/29.16.3439.
^ 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. PMID 15467736. doi:10.1038/sj.onc.1208128.

External links[edit]

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.

[1] "Human PubMed Reference:".

[2] "Mouse PubMed Reference:".

[pmid10220385-3] 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. PMC 21783 . PMID 10220385. doi:10.1073/pnas.96.9.4868.

[pmid10206986-4] 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. PMID 10206986. doi:10.1074/jbc.274.17.11713.

[entrez-5] "Entrez Gene: HDAC4 histone deacetylase 4".

[6] 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. PMID 17610967. doi:10.1016/j.bbamcr.2007.05.016.

[7] Protein for Sight, Scientific American, 300, 3 (March 2009), p. 23

[pmid19131628-8] Chen B, Cepko CL (January 2009). "HDAC4 regulates neuronal survival in normal and diseased retinas". Science. 323 (5911): 256–9. PMC 3339762 . PMID 19131628. doi:10.1126/science.1166226.

[pmid11929873-9] 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. PMID 11929873. doi:10.1074/jbc.M201736200.

[pmid17371797-10] 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. PMID 17371797. doi:10.1096/fj.06-7548com.

[11] Micheli L, D'Andrea G, Leonardi L & Tirone F (2017). "HDAC1, HDAC4, and HDAC9 Bind to PC3/Tis21/Btg2 and Are Required for Its Inhibition of Cell Cycle Progression and Cyclin D1 Expression". Journal of cellular physiology. 232 (7): 1696–1707. PMID 27333946. doi:10.1002/jcp.25467.

[pmid12242305-12] 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. PMC 139799 . PMID 12242305. doi:10.1128/mcb.22.20.7302-7312.2002.

[pmid14668799-13] 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. PMID 14668799. doi:10.1038/sj.onc.1206902.

[pmid11804585-14] 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. PMID 11804585. doi:10.1016/s1097-2765(01)00429-4.

[pmid10869435-15] 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. PMC 16631 . PMID 10869435. doi:10.1073/pnas.140199597.

[pmid11466315-16] 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. PMID 11466315. doi:10.1074/jbc.M104935200.

[pmid11114188-17] 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. PMC 18918 . PMID 11114188. doi:10.1073/pnas.250494697.

[pmid10523670-18] 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. PMC 84849 . PMID 10523670. doi:10.1128/mcb.19.11.7816.

[pmid11486037-19] Wang AH, Yang XJ (September 2001). "Histone deacetylase 4 possesses intrinsic nuclear import and export signals". Mol. Cell. Biol. 21 (17): 5992–6005. PMC 87317 . PMID 11486037. doi:10.1128/mcb.21.17.5992-6005.2001.

[pmid10487761-20] 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. PMC 1171580 . PMID 10487761. doi:10.1093/emboj/18.18.5099.

[pmid10748098-21] 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. PMID 10748098. doi:10.1074/jbc.M908437199.

[pmid10640275-22] 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.

[pmid12943985-23] 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. PMID 12943985. doi:10.1016/s0303-7207(03)00254-5.

[pmid11463856-24] 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. PMID 11463856. doi:10.1210/mend.15.8.0682.

[pmid11504882-25] 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. PMC 55849 . PMID 11504882. doi:10.1093/nar/29.16.3439.

[pmid15467736-26] 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. PMID 15467736. doi:10.1038/sj.onc.1208128.

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v t e Hydrolases: carbon-nitrogen non-peptide (EC 3.5)
3.5.1: Linear amides / Amidohydrolases	Asparaginase Glutaminase Urease Biotinidase Aspartoacylase Ceramidase Aspartylglucosaminidase Fatty acid amide hydrolase Histone deacetylase Sirtuin
3.5.2: Cyclic amides/ Amidohydrolases	Barbiturase Beta-lactamase
3.5.3: Linear amidines/ Ureohydrolases	Arginase Agmatinase Protein-arginine deiminase
3.5.4: Cyclic amidines/ Aminohydrolases	Guanine deaminase Adenosine deaminase AMP deaminase Inosine monophosphate synthase DCMP deaminase GTP cyclohydrolase I Cytidine deaminase AICDA Activation-induced cytidine deaminase
3.5.5: Nitriles/ Aminohydrolases	Nitrilase
3.5.99: Other	Riboflavinase Thiaminase II

v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list)

HDAC4

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