Regional and subcellular distribution of HDAC4 in mouse brain
Abstract
Histone deacetylases (HDACs) are part of a system that links epigenetic control of gene expression to a variety of environmental stimuli. Some HDACs, including HDAC4, shuttle between the cytoplasm and nucleus in response to physiological cues such as calcium signaling. HDAC4 mRNA is enriched in the brain, but the regional and subcellular protein expression pattern of HDAC4 is not known. Here we show that HDAC4 is more highly expressed in some brain regions than in others. HDAC4 is present in the perikaryial cytoplasm of most neurons but its nuclear localization is variable. In some areas, such as the dentate gyrus, nuclear expression is not detectable, whereas in other areas some neuronal nuclei contain HDAC4 immunoreactivity whereas others do not. In the cytoplasm, HDAC4 immunoreactivity is punctate. Some of these puncta are present in dendritic spines where the strongest immunoreactivity is associated with the postsynaptic density. These data demonstrate that the regional and subcellular distribution of HDAC4 is heterogeneous and raise the possibilities that HDAC4 acts on nonhistone substrates in dendritic spines or that it shuttles between spine and nucleus to coordinate synaptic activity with gene expression. J. Comp. Neurol. 518:722–740, 2010. © 2009 Wiley‐Liss, Inc.
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HDAC4 exhibits high expression levels in the forebrain and is enriched in neurons.
“HDAC4 exhibits high expression levels in the forebrain and is enriched in neurons.138,139”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [139]
HDAC4 is expressed at high levels in the neuronal cytoplasm and dendritic spines.
“HDAC4 is expressed at high levels in the neuronal cytoplasm and dendritic spines.”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [54]
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“,139 It shuttles between the cell nucleus and cytoplasm.”
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“These observations are in agreement with previous studies on the subcellular localization of HDACs in the brain (39, 47).”
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“Given that a pool of HDAC4 localizes to the post-synaptic density (Darcy et al., 2010), these associations are worth further investigation.”
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BackgroundThe role of nuclear Ca2+ in maintaining neuronal homeostasis and brain health
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“As a member of group II HDACs, HDAC4 is closely linked to many disease processes—including cancer, leukemia, diabetes, infection, and cardiac disease [13–18]— and is also highly expressed in the brain where it plays an important role in brain functioning [19–22].”
BackgroundThomas, J., Garg, M. L., & Smith, D. W. (2013) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2013.11.005 · Cited by 39 · see citing works
“demonstrated localization of Hdac4 in dendritic spines, indicating Hdac4 may play a direct, perhaps non-histone related role in coordinating synaptic function and gene transcription [33].”
BackgroundChen, Y., Wang, Y., Modrusan, Z. D., Sheng, M., & Kaminker, J. S. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.0569-14.2014 · Cited by 37 · see citing works
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“Given the predominant nonnuclear localization, particularly the concentration ofHDAC4 at dendritic spines (Darcy et al. 2010), we hypothesize that cytoplasmic HDAC4 is required in memory formation; however, the mechanisms through which HDAC4 acts outside the nucleus are unknown.”
BackgroundInfluentialATM Protein Kinase: Old and New Implications in Neuronal Pathways and Brain Circuitry
Pizzamiglio, L., Focchi, E., & Antonucci, F. (2020) · Cells · doi:10.3390/cells9091969 · Cited by 36 · see citing works
“HDAC4 localization depends on its phosphorylation state: the dephosphorylated form accumulates in the nucleus, whereas it must be phosphorylated to stay in the cytoplasm [112].”
BackgroundCatalà-Solsona, J., Miñano-Molina, A. J., & Rodrı́guez-Álvarez, J. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.786226 · Cited by 35 · see citing works
“Although HDAC4 is mainly located in the neuronal cytoplasm with a more variable nuclear presence, immunohistochemistry studies have shown a strong PSD immunoreactivity in dendritic spines (Darcy et al., 2010).”
BackgroundLitke, C., Bading, H., & Mauceri, D. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra117.001613 · Cited by 33 · see citing works
“Among class IIa HDACs, HDAC4 is highly expressed in the rodent hippocampus and forebrain regions (16); under basal conditions, it is predominantly localized in the cytoplasm of neurons (17).”
BackgroundSynaptically Localized Transcriptional Regulators in Memory Formation
Uchida, S., & Shumyatsky, G. P. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2017.07.023 · Cited by 33 · see citing works
“HDAC4 is abundant in neurons, where it is predominantly localized to cytoplasm and dendritic spines (Darcy et al., 2010; Grozinger et al., 1999; Wang et al., 1999).”
Stroke Induces Nuclear Shuttling of Histone Deacetylase 4
Kassis, H., Shehadah, A., Chopp, M., Roberts, C. J., & Zhang, Z. G. (2015) · Stroke · doi:10.1161/strokeaha.115.009046 · Cited by 31 · see citing works
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“, 1991), many neuroscientists have applied detergent to detect and enhance the immunoreactivity of molecules of interest (Shigemoto et al., 1997; Sugita et al., 2001; Kubota et al., 2007; Melchitzky and Lewis, 2008; Torres-Reveron et al., 2009; Chiu et al., 2010; Darcy et al., 2010; Eggan et al., 2010; Chen et al., 20…”
BackgroundHDAC4 Does Not Act as a Protein Deacetylase in the Postnatal Murine Brain In Vivo
Mielcarek, M., Seredenina, T. S., Stokes, M. P., Osborne, G. F., Landles, C., Inuabasi, L., Franklin, S., Silva, J. C., Luthi‐Carter, R., Beaumont, V., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0080849 · Cited by 30 · see citing works
“HDAC4 is highly expressed in the mouse brain as compared to the other class IIa enzymes [7] with the highest expression occurring during early postnatal life [8].”
BackgroundRole of Phosphorylated HDAC4 in Stroke-Induced Angiogenesis
Liu, J., Zhou, X., Li, Q., Zhou, S.-M., Hu, B., Hu, G., Niu, X., Guo, S., Wang, Y., & Deng, Z. (2017) · BioMed Research International · doi:10.1155/2017/2957538 · Cited by 30 · see citing works
“Previous studies have demonstrated that HDAC4 is highly expressed in the brain [4], and neuronal activity depends on the nucleocytoplasmic shuttling of HDAC4 [5].”
BackgroundDemyanenko, S. V., Berezhnaya, E. V., Neginskaya, M. A., Rodkin, S., Dzreyan, V., & Pitinova, M. (2019) · Journal of Cellular Biochemistry · doi:10.1002/jcb.29266 · Cited by 29 · see citing works
“neuronal nuclei.(24) It is known that ischemia in the brain leads to nuclear translocation of HDAC4.”
BackgroundCharacterization of brain cell nuclei with decondensed chromatin
Yu, P., McKinney, E. C., Kandasamy, M. K., Albert, A. L., & Meagher, R. B. (2014) · Developmental Neurobiology · doi:10.1002/dneu.22245 · Cited by 25 · see citing works
“The expression of the non-sirtuin family of HDACs is well-characterized in the rodent brain (Broide et al., 2007; Liu et al., 2008; Darcy et al., 2010; Yao et al., 2013).”
BackgroundDemyanenko, S. V., Dzreyan, V., & Uzdensky, A. B. (2020) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2020.06.010 · Cited by 23 · see citing works
Cytoplasmic HDAC4 recovers synaptic function in the 3×Tg mouse model of Alzheimer's disease
Colussi, C., Aceto, G., Ripoli, C., Bertozzi, A., Puma, D. D. L., Paccosi, E., D’Ascenzo, M., & Grassi, C. (2022) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12861 · Cited by 19 · see citing works
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Histone deacetylase 4 (HDAC4): a new player in anorexia nervosa?
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HDAC4 is expressed on multiple T cell lineages but dispensable for their development and function
Liu, Q., Zhang, X., Yin, C., Chen, X., Zhang, Z., Brown, S. L., Xie, H., Zhou, L., & Mi, Q. (2017) · Oncotarget · doi:10.18632/oncotarget.15077 · Cited by 16 · see citing works
“HDAC4, one member of the tissue-specific Class II HDACs, is highly expressed in neurons [29] and bone mass, and plays an essential role in maintaining neuronal survival [30] and chondrocyte hypertrophy [31].”
BackgroundCarbone, C., Brancato, A., Adinolfi, A., Russo, S. L. M. L., Alleva, E., Cannizzaro, C., & Adriani, W. (2020) · Neuroscience · doi:10.1016/j.neuroscience.2020.03.005 · Cited by 16 · see citing works
ATM and the epigenetics of the neuronal genome
Herrup, K. (2013) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2013.05.005 · Cited by 15 · see citing works
“It is a predominantly cytoplasmic protein in neurons (69, 72, 73).”
BackgroundThe dark side of HDAC inhibition in ALS
Boutillier, A., Tzeplaeff, L., & Dupuis, L. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.02.039 · Cited by 14 · see citing works
“In neurons, HDAC4 is predominantly cytoplasmic, particularly concentrated indendritic spines [7].”
BackgroundNash, B., Festa, L. K., Lin, C., & Meucci, O. (2019) · Brain Research · doi:10.1016/j.brainres.2019.146409 · Cited by 14 · see citing works
“HDAC4 phosphorylation and nuclear export depends on neuronal activity and calcium influx, and cytoplasmic HDAC4 is expressed in some dendritic spines (Darcy et al., 2010).”
BackgroundDDIT4 gene expression is switched on by a new HDAC4 function in ataxia telangiectasia
Ricci, A., Galluzzi, L., Magnani, M., & Menotta, M. (2019) · The FASEB Journal · doi:10.1096/fj.201902039r · Cited by 14 · see citing works
The Role of Epigenomics in the Neurodegeneration of Ataxia-Telangiectasia
Li, J., & Jiang, D. (2015) · Epigenomics · doi:10.2217/epi.14.81 · Cited by 13 · see citing works
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Investigation of differential HDAC4 methylation patterns in eating disorders
Subramanian, S., Braun, P., Han, S., & Potash, J. B. (2017) · Psychiatric Genetics · doi:10.1097/ypg.0000000000000189 · Cited by 9 · see citing works
“HDAC4 is involved in energy homeostasis and neuronal plasticity, with widespread distribution in the brain (Darcy et al., 2010; Sando et al., 2012; Clocchiatti et al., 2013).”
Expression characterization and the promoter activity analysis of zebrafish hdac4
Zhu, K., Wang, H., Gul, Y., Zhao, Y., Wang, W., Liu, S., & Wang, M. (2011) · Fish Physiology and Biochemistry · doi:10.1007/s10695-011-9540-x · Cited by 8 · see citing works
“Previous research shows a complex role of hdac4 in brain which is region-specific for germane to synaptic activity and gene expression (Michael et al. 2010).”
BackgroundTurkman, N., Xu, S., Huang, C.-H., Eyermann, C. E., Salino, J., & Khan, P. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c02064 · Cited by 7 · see citing works
Epigenetic Mechanisms of Ischemic Stroke
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“Another study demonstrated a more variable localization of HDAC 4 in normal PN ranging from nuclear to cytoplasmic and including some PN with HDAC 4 in both the nucleus and cytoplasm (Darcy et al., 2010).”
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BindingDB Entry 50008262: Recent advances in class IIa histone deacetylases research.
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- Authors
- Darcy, M. J., Calvin, K., Cavnar, K., & Ouimet, C. C.
- Affiliations
- Florida State University (US)
- Corresponding author
- Ouimet, Charles C.
- Venue
- Journal of Comparative Neurology
- Publisher
- Wiley
- Published
- 2009-12-27
- Volume
- 518
- Issue
- 5
- Pages
- 722-740
- ISSN
- 0021-9967 (ISSN-L)
- 1096-9861
- OpenAlex
- W1565308878
- Cited by
- 69
- References
- 64
- Citations by year
- 2025: 1 · 2023: 2 · 2022: 3 · 2021: 3 · 2020: 6 · 2019: 11 · 2018: 2 · 2017: 8 · 2016: 5 · 2015: 5 · 2014: 3 · 2013: 10 · 2012: 5
- FWCI
- 1.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Comparative Neurology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- HDAC4, histone deacetylase, subcellular localization, dendritic spines, postsynaptic density, nucleocytoplasmic shuttling, epigenetic regulation, dentate gyrus, neurons, calcium signaling
- MeSH terms
- Animals, Brain, Brain Mapping, Cell Compartmentation, Cell Line, Cell Nucleus, Cytoplasm, Gene Expression Regulation, Histone Deacetylases, Humans, Immunohistochemistry, Male, Neurons, Organ Culture Techniques, Synapses, Transfection, Microscopy, Immunoelectron, Microscopy, Confocal, Dentate Gyrus, Biolistics, Dendritic Spines, Mice, Rats
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