# HDAC4

## Overview
HDAC4 (histone deacetylase 4) is a gene that encodes a class IIa histone deacetylase protein, which plays a pivotal role in the regulation of gene expression through chromatin remodeling. The HDAC4 protein is involved in transcriptional repression by removing acetyl groups from histone proteins, leading to chromatin condensation and reduced gene expression. It functions as a transcriptional corepressor and is implicated in various biological processes, including muscle differentiation, neuronal development, and synaptic plasticity (Sando2012HDAC4; Wang1999HDAC4). HDAC4 is expressed in several tissues, such as skeletal muscle, brain, and heart, where it interacts with transcription factors like MEF2A and MEF2C to modulate gene expression (Miska1999HDAC4). The protein's activity and localization are regulated by post-translational modifications, including phosphorylation, which influences its shuttling between the nucleus and cytoplasm (Chawla2003Neuronal). HDAC4's involvement in neuroprotection and its association with various clinical conditions, such as Brachydactyly mental retardation syndrome and neurodegenerative diseases, underscore its significance as a potential therapeutic target (Mielcarek2015HDAC4; Majdzadeh2008HDAC4).

## Structure
HDAC4 is a member of the class IIa histone deacetylases, characterized by distinct structural domains. The protein contains an N-terminal domain, which includes a glutamine-rich region forming a four-helix bundle. This domain is involved in protein-protein interactions and is responsive to calcium signals (Guo2007Crystal). The N-terminal domain can form tetramers, with interactions mediated by polar networks and hydrophobic patches (Guo2007Crystal).

The C-terminal domain of HDAC4 contains the catalytic deacetylase domain, which is homologous to yeast HDA1. This domain is responsible for the enzyme's deacetylase activity, although HDAC4 itself lacks intrinsic activity and requires complex formation with other proteins for functionality (Wang1999HDAC4). The catalytic domain features a structural zinc-binding domain, crucial for its enzymatic function and interaction with co-repressor complexes. This domain exhibits flexibility, adopting different conformations in the presence or absence of inhibitors (Bottomley2008Structural).

HDAC4 undergoes post-translational modifications, such as phosphorylation, which influence its cellular localization and activity. The protein also exists in multiple splice variant isoforms, contributing to its diverse functional roles (Bottomley2008Structural).

## Function
HDAC4 (histone deacetylase 4) is a class IIa histone deacetylase that plays a significant role in transcriptional repression by removing acetyl groups from histone proteins, leading to chromatin condensation and reduced gene expression. It functions as a transcriptional corepressor and is involved in various cellular processes, including muscle differentiation, neuronal development, and synaptic plasticity (Sando2012HDAC4; Wang1999HDAC4).

In healthy human cells, HDAC4 is expressed in tissues such as skeletal muscle, brain, and heart, where it regulates gene expression by interacting with transcription factors like MEF2A and MEF2C. This interaction leads to the repression of MEF2-dependent transcription, which is crucial for muscle differentiation and neuronal function (Wang1999HDAC4; Miska1999HDAC4). HDAC4 shuttles between the nucleus and cytoplasm, a process regulated by synaptic activity and calcium signaling, which influences its role in gene regulation (Chawla2003Neuronal).

HDAC4 also plays a protective role in neurons by inhibiting cell cycle progression and preventing apoptosis, which is essential for neuroprotection and the prevention of neurodegenerative diseases (Majdzadeh2008HDAC4). Its activity is modulated by phosphorylation, affecting its localization and function within the cell (Sando2012HDAC4).

## Clinical Significance
Mutations and alterations in the HDAC4 gene are associated with several clinical conditions. A specific mutation involving a single cytosine insertion (+C) in the HDAC4 gene is linked to Brachydactyly mental retardation syndrome (BDMR). This mutation results in a truncated form of HDAC4 that acts as a gain-of-function nuclear repressor, leading to cognitive abnormalities due to its transcriptional repression activity (Sando2012HDAC4). BDMR is characterized by developmental delay, facial dysmorphism, and sometimes brachydactyly, with HDAC4 haploinsufficiency being a major contributor to these phenotypes (Le2019Genotype).

HDAC4 is also implicated in 2q37 deletion syndrome, where its deletion or reduced expression is associated with a range of phenotypic features, including developmental delay, obesity, and craniofacial dysmorphism. This syndrome shows phenotypic overlap with other neurodevelopmental conditions, highlighting the significant role of HDAC4 in neurodevelopmental and craniofacial development (Le2019Genotype).

In neurodegenerative diseases, increased HDAC4 expression is linked to conditions such as Huntington's disease, Alzheimer's disease, and Parkinson's disease. In these disorders, HDAC4 is associated with synaptic dysfunction and neuronal loss, making it a potential therapeutic target (Mielcarek2015HDAC4).

## Interactions
HDAC4 interacts with several proteins, influencing its role in transcriptional repression and cellular localization. It forms complexes with HDAC3, a nuclear protein, through the SMRT/N-CoR complex, which is essential for its enzymatic activity. This interaction is crucial as HDAC4 lacks intrinsic enzymatic activity and relies on HDAC3 for its function (Fischle2002Enzymatic). HDAC4 also associates with 14-3-3 proteins, specifically the β and ε isoforms, in a phosphorylation-dependent manner. This interaction sequesters HDAC4 in the cytoplasm, preventing it from repressing transcription by blocking its nuclear import (Grozinger2000Regulation).

HDAC4 interacts with transcription factors such as MEF2C, Runx2, and SRF, modulating their transcriptional activities. The interaction with MEF2C is particularly significant, as HDAC4 represses MEF2C-dependent transcription, which is crucial for muscle cell differentiation and cellular proliferation (Wang1999HDAC4; Miska1999HDAC4). HDAC4's interaction with these transcription factors is influenced by its phosphorylation state and caspase processing, which affect its subcellular localization and repressive capabilities (Paroni2007Dephosphorylation).


## References


[1. (Chawla2003Neuronal) Sangeeta Chawla, Peter Vanhoutte, Fiona J. L. Arnold, Christopher L.‐H. Huang, and Hilmar Bading. Neuronal activity‐dependent nucleocytoplasmic shuttling of hdac4 and hdac5. Journal of Neurochemistry, 85(1):151–159, March 2003. URL: http://dx.doi.org/10.1046/j.1471-4159.2003.01648.x, doi:10.1046/j.1471-4159.2003.01648.x. This article has 246 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1046/j.1471-4159.2003.01648.x)

[2. (Grozinger2000Regulation) Christina M. Grozinger and Stuart L. Schreiber. Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3- 3-dependent cellular localization. Proceedings of the National Academy of Sciences, 97(14):7835–7840, June 2000. URL: http://dx.doi.org/10.1073/pnas.140199597, doi:10.1073/pnas.140199597. This article has 485 citations.](https://doi.org/10.1073/pnas.140199597)

[3. (Bottomley2008Structural) Matthew J. Bottomley, Paola Lo Surdo, Paolo Di Giovine, Agostino Cirillo, Rita Scarpelli, Federica Ferrigno, Philip Jones, Petra Neddermann, Raffaele De Francesco, Christian Steinkühler, Paola Gallinari, and Andrea Carfí. 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, September 2008. URL: http://dx.doi.org/10.1074/jbc.m803514200, doi:10.1074/jbc.m803514200. This article has 364 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m803514200)

[4. (Le2019Genotype) Trang N. Le, Stephen R. Williams, Joseph T. Alaimo, and Sarah H. Elsea. Genotype and phenotype correlation in 103 individuals with 2q37 deletion syndrome reveals incomplete penetrance and supports hdac4 as the primary genetic contributor. American Journal of Medical Genetics Part A, 179(5):782–791, March 2019. URL: http://dx.doi.org/10.1002/ajmg.a.61089, doi:10.1002/ajmg.a.61089. This article has 29 citations.](https://doi.org/10.1002/ajmg.a.61089)

[5. (Paroni2007Dephosphorylation) Gabriela Paroni, Alessandra Fontanini, Nadia Cernotta, Carmela Foti, Mahesh P. Gupta, Xiang-Jiao Yang, Dario Fasino, and Claudio Brancolini. Dephosphorylation and caspase processing generate distinct nuclear pools of histone deacetylase 4. Molecular and Cellular Biology, 27(19):6718–6732, October 2007. URL: http://dx.doi.org/10.1128/mcb.00853-07, doi:10.1128/mcb.00853-07. This article has 35 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/mcb.00853-07)

[6. (Sando2012HDAC4) Richard Sando, Natalia Gounko, Simon Pieraut, Lujian Liao, John Yates, and Anton Maximov. Hdac4 governs a transcriptional program essential for synaptic plasticity and memory. Cell, 151(4):821–834, November 2012. URL: http://dx.doi.org/10.1016/j.cell.2012.09.037, doi:10.1016/j.cell.2012.09.037. This article has 221 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.cell.2012.09.037)

[7. (Wang1999HDAC4) Audrey H. Wang, Nicholas R. Bertos, Marko Vezmar, Nadine Pelletier, Milena Crosato, Henry H. Heng, John Th’ng, Jiahuai Han, and Xiang-Jiao Yang. Hdac4, a human histone deacetylase related to yeast hda1, is a transcriptional corepressor. Molecular and Cellular Biology, 19(11):7816–7827, November 1999. URL: http://dx.doi.org/10.1128/mcb.19.11.7816, doi:10.1128/mcb.19.11.7816. This article has 239 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/mcb.19.11.7816)

[8. (Guo2007Crystal) Liang Guo, Aidong Han, Darren L. Bates, Jue Cao, and Lin Chen. Crystal structure of a conserved n-terminal domain of histone deacetylase 4 reveals functional insights into glutamine-rich domains. Proceedings of the National Academy of Sciences, 104(11):4297–4302, March 2007. URL: http://dx.doi.org/10.1073/pnas.0608041104, doi:10.1073/pnas.0608041104. This article has 62 citations.](https://doi.org/10.1073/pnas.0608041104)

[9. (Fischle2002Enzymatic) Wolfgang Fischle, Franck Dequiedt, Michael J Hendzel, Matthew G Guenther, Mitchell A Lazar, Wolfgang Voelter, and Eric Verdin. Enzymatic activity associated with class ii hdacs is dependent on a multiprotein complex containing hdac3 and smrt/n-cor. Molecular Cell, 9(1):45–57, January 2002. URL: http://dx.doi.org/10.1016/s1097-2765(01)00429-4, doi:10.1016/s1097-2765(01)00429-4. This article has 605 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/s1097-2765(01)00429-4)

[10. (Majdzadeh2008HDAC4) Nazanin Majdzadeh, Lulu Wang, Brad E. Morrison, Rhonda Bassel‐Duby, Eric N. Olson, and Santosh R. D’Mello. Hdac4 inhibits cell‐cycle progression and protects neurons from cell death. Developmental Neurobiology, 68(8):1076–1092, May 2008. URL: http://dx.doi.org/10.1002/dneu.20637, doi:10.1002/dneu.20637. This article has 113 citations and is from a peer-reviewed journal.](https://doi.org/10.1002/dneu.20637)

[11. (Mielcarek2015HDAC4) Michal Mielcarek, Daniel Zielonka, Alisia Carnemolla, Jerzy T. Marcinkowski, and Fabien Guidez. Hdac4 as a potential therapeutic target in neurodegenerative diseases: a summary of recent achievements. Frontiers in Cellular Neuroscience, February 2015. URL: http://dx.doi.org/10.3389/fncel.2015.00042, doi:10.3389/fncel.2015.00042. This article has 87 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fncel.2015.00042)

[12. (Miska1999HDAC4) E. A. Miska. Hdac4 deacetylase associates with and represses the mef2 transcription factor. The EMBO Journal, 18(18):5099–5107, September 1999. URL: http://dx.doi.org/10.1093/emboj/18.18.5099, doi:10.1093/emboj/18.18.5099. This article has 452 citations.](https://doi.org/10.1093/emboj/18.18.5099)