HDAC9

Histone deacetylase 9 is an enzyme that in humans is encoded by the HDAC9 gene.^[5][6][7]

HDAC9
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1TQE
Identifiers
Aliases	HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR, histone deacetylase 9
External IDs	OMIM: 606543 MGI: 1931221 HomoloGene: 128578 GeneCards: HDAC9
Gene location (Human) Chr. Chromosome 7 (human)^[1] Band 7p21.1 Start 18,086,949 bp^[1] End 19,002,416 bp^[1]
Gene location (Mouse) Chr. Chromosome 12 (mouse)^[2] Band 12|12 A3 Start 34,097,579 bp^[2] End 34,967,094 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in oocyte monocyte secondary oocyte endothelial cell parotid gland ganglionic eminence corpus callosum superficial temporal artery Achilles tendon bone marrow cells Top expressed in interventricular septum secondary oocyte Region I of hippocampus proper ascending aorta visual cortex piriform cortex left ventricle olfactory bulb lateral geniculate nucleus atrioventricular valve More reference expression data BioGPS n/a
Gene ontology Molecular function NAD-dependent histone deacetylase activity (H3-K14 specific) transcription corepressor activity histone deacetylase activity protein deacetylase activity transcription factor binding histone deacetylase binding metal ion binding protein binding hydrolase activity protein kinase C binding histone deacetylase activity (H4-K16 specific) Cellular component cytoplasm histone deacetylase complex transcription regulator complex nucleoplasm nucleus histone methyltransferase complex Biological process histone H3 deacetylation peptidyl-lysine deacetylation regulation of transcription, DNA-templated positive regulation of cell migration involved in sprouting angiogenesis response to amphetamine negative regulation of transcription by RNA polymerase II regulation of striated muscle cell differentiation transcription, DNA-templated B cell activation heart development histone H4 deacetylation neuron differentiation cellular response to insulin stimulus regulation of skeletal muscle fiber development B cell differentiation inflammatory response negative regulation of transcription, DNA-templated chromatin organization histone deacetylation cholesterol homeostasis negative regulation of lipoprotein lipase activity histone H4-K16 deacetylation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 9734 79221 Ensembl ENSG00000048052 ENSMUSG00000004698 UniProt Q9UKV0 Q99N13 RefSeq (mRNA) NM_001204144 NM_001204145 NM_001204146 NM_001204147 NM_001204148 NM_014707 NM_058176 NM_058177 NM_178423 NM_178425 NM_001321868 NM_001321869 NM_001321870 NM_001321871 NM_001321872 NM_001321873 NM_001321874 NM_001321875 NM_001321876 NM_001321877 NM_001321878 NM_001321879 NM_001321884 NM_001321885 NM_001321886 NM_001321887 NM_001321888 NM_001321889 NM_001321890 NM_001321891 NM_001321893 NM_001321894 NM_001321895 NM_001321896 NM_001321897 NM_001321898 NM_001321899 NM_001321900 NM_001321901 NM_001321902 NM_001271386 NM_024124 RefSeq (protein) NP_001191073 NP_001191074 NP_001191075 NP_001191076 NP_001191077 NP_001308797 NP_001308798 NP_001308799 NP_001308800 NP_001308801 NP_001308802 NP_001308803 NP_001308804 NP_001308805 NP_001308806 NP_001308807 NP_001308808 NP_001308813 NP_001308814 NP_001308815 NP_001308816 NP_001308817 NP_001308818 NP_001308819 NP_001308820 NP_001308822 NP_001308823 NP_001308824 NP_001308825 NP_001308826 NP_001308827 NP_001308828 NP_001308829 NP_001308830 NP_001308831 NP_055522 NP_478056 NP_848510 NP_848512 NP_001258315 NP_077038 Location (UCSC) Chr 7: 18.09 – 19 Mb Chr 12: 34.1 – 34.97 Mb PubMed search ^[3] ^[4]
Wikidata
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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 has sequence homology to members of the histone deacetylase family. This gene is orthologous to the Xenopus and mouse MITR genes. The MITR protein lacks the histone deacetylase catalytic domain. It represses MEF2 activity through recruitment of multicomponent corepressor complexes that include CtBP and HDACs. This encoded protein may play a role in hematopoiesis. Multiple alternatively spliced transcripts have been described for this gene but the full-length nature of some of them has not been determined.^[7]

Histone deacetylase 9 (HDAC9), a member of class II HDACs, regulates a wide variety of normal and abnormal physiological functions.

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 has sequence homology to members of the histone deacetylase family. This gene is orthologous to the Xenopus and mouse MITR genes. The MITR protein lacks the histone deacetylase catalytic domain. It represses MEF2 activity through recruitment of multicomponent corepressor complexes that include CtBP and HDACs. This encoded protein may play a role in hematopoiesis. Multiple alternatively spliced transcripts have been described for this gene but the full-length nature of some of them has not been determined.

Research

intracranial aneurysm

HDAC9 and BCL2L11 are upregulated while miR-92a was downregulated in clinical samples and rat models of intracranial aneurysm (IA). HDAC9 inhibition or miR-92a elevation improved pathological changes and repressed apoptosis and expression of MMP-2, MMP-9, VEGF and inflammatory factors in vascular tissues from IA rats. Oppositely, HDAC9 overexpression or miR-92a reduction had contrary effects. miR-92a downregulation reversed the effect of silenced HDAC9 on IA rats. HDAC9 inhibition upregulates miR-92a to repress the progression of IA via silencing BCL2L11.^[8]

Data partially confirmed earlier results and showed that variants in CDKN2B-AS1, RP1, and HDAC9 could be genetic susceptibility factors for IA in a Chinese population.^[9]

ischemic brain injury

Histone deacetylase 9 (HDAC9) has been reported to be elevated in ischemic brain injury, but its mechanism in stroke is still enigmatic. CTCF inhibited miR-383-5p expression via its enrichment in the promoter region of miR-383-5p, whereas the miR-383-5p targeted and inhibited HDAC9 expression.^[10] In the oxygen glucose deprivation cell model and the middle cerebral artery occlusion rat model, elevation of HDAC9 is regulated by the CTCF/miR-383-5p/HDAC9 pathway mediated apoptosis induced by endoplasmic reticulum stress, while reduction of HDAC9 alleviated apoptosis and the symptoms of cerebral infarction in MCAO rats. Thus, the CTCF/miR-383-5p/HDAC9 pathway may present a target for drug development against ischemic brain injury 6).^[11]

HDAC9 is highly expressed in MCAO mice and oxygen glucose deprivation (OGD) stimulated cells. Silencing of HDAC9 inhibited neuronal apoptosis and inflammatory factor release in vitro. HDAC9 downregulated miR-20a by enriching in its promoter region, while silencing of HDCA9 promoted miR-20a expression. miR-20a targeted Neurod1 and down-regulated its expression. Silencing of HDAC9 diminished OGD-induced neuronal apoptosis and inflammatory factor release in vitro as well as ischemic brain injury in vivo by regulating the miR-20a/NeuroD1 signaling. HDAC9 silencing may retard ischemic brain injury through miR-20a/Neurod1 signaling.^[11]

Glioblastoma

HDAC9 is over-expressed in prognostically poor glioblastoma patients. Knockdown HDAC9 decreased proliferation in vitro and tumor formation in vivo. HDAC9 accelerated cell cycle in part by potentiating the EGFR signaling pathway. Also, HDAC9 interacted with TAZ, a key downstream effector of Hippo pathway. Knockdown of HDAC9 decreased the expression of TAZ. We found that overexpressed TAZ in HDAC9-knockdown cells abrogated the effects induced by HDAC9 silencing both in vitro and in vivo. HDAC9 promotes tumor formation of glioblastoma via TAZ-mediated EGFR pathway activation.^[12]

Saethre-Chotzen syndrome

HDAC9 was suggested to contribute to developmental delay in Saethre-Chotzen syndrome (SCS) patients with 7p21 mirodeletions.^[13]

Motor innervation control of gene expression

Motor innervation controls chromatin acetylation in skeletal muscle and that histone deacetylase 9 (HDAC9) is a signal-responsive transcriptional repressor which is downregulated upon denervation, with consequent upregulation of chromatin acetylation and AChR expression. Forced expression of Hdac9 in denervated muscle prevents upregulation of activity-dependent genes and chromatin acetylation by linking myocyte enhancer factor 2 (MEF2) and class I HDACs. By contrast, Hdac9-null mice are supersensitive to denervation-induced changes in gene expression and show chromatin hyperacetylation and delayed perinatal downregulation of myogenin, an activator of AChR genes. These findings show a molecular mechanism to account for the control of chromatin acetylation by presynaptic neurons and the activity-dependent regulation of skeletal muscle genes by motor innervation.^[14]

Interactions

HDAC9 has been shown to interact with:

• IKK1,^[15]
• IKK2,^[15]
• CBX5,^[16]
• HDAC3,^[17][18]
• BTG2,^[19]
• Myocyte-specific enhancer factor 2A^[20][21]
• Nuclear receptor co-repressor 1,^[17]
• SIN3A,^[17][22] and
• SUV39H1.^[16]

See also

• Histone deacetylase

References

1. GRCh38: Ensembl release 89: ENSG00000048052 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000004698 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Wang AH, Bertos NR, Vezmar M, Pelletier N, Crosato M, Heng HH, et al. (November 1999). "HDAC4, a human histone deacetylase related to yeast HDA1, is a transcriptional corepressor". Molecular and Cellular Biology. 19 (11): 7816–7827. doi:10.1128/mcb.19.11.7816. PMC 84849. PMID 10523670.
6. Sparrow DB, Miska EA, Langley E, Reynaud-Deonauth S, Kotecha S, Towers N, et al. (September 1999). "MEF-2 function is modified by a novel co-repressor, MITR". The EMBO Journal. 18 (18): 5085–5098. doi:10.1093/emboj/18.18.5085. PMC 1171579. PMID 10487760.
7. "Entrez Gene: HDAC9 histone deacetylase 9".
8. Cai Y, Huang D, Ma W, Wang M, Qin Q, Jiang Z, Liu M (August 2021). "Histone deacetylase 9 inhibition upregulates microRNA-92a to repress the progression of intracranial aneurysm via silencing Bcl-2-like protein 11". Journal of Drug Targeting. 29 (7): 761–770. doi:10.1080/1061186X.2021.1878365. PMID 33480300. S2CID 231678641.
9. Li B, Hu C, Liu J, Liao X, Xun J, Xiao M, Yan J (July 2019). "Associations among Genetic Variants and Intracranial Aneurysm in a Chinese Population". Yonsei Medical Journal. 60 (7): 651–658. doi:10.3349/ymj.2019.60.7.651. PMC 6597466. PMID 31250579.
10. Shen J, Han Q, Li W, Chen X, Lu J, Zheng J, Xue S (August 2022). "miR-383-5p Regulated by the Transcription Factor CTCF Affects Neuronal Impairment in Cerebral Ischemia by Mediating Deacetylase HDAC9 Activity". Molecular Neurobiology. 59 (10): 6307–6320. doi:10.1007/s12035-022-02840-4. PMID 35927544. S2CID 251349105.
11. Zhong L, Yan J, Li H, Meng L (2020). "HDAC9 Silencing Exerts Neuroprotection Against Ischemic Brain Injury via miR-20a-Dependent Downregulation of NeuroD1". Frontiers in Cellular Neuroscience. 14: 544285. doi:10.3389/fncel.2020.544285. PMC 7873949. PMID 33584204.
12. Yang R, Wu Y, Wang M, Sun Z, Zou J, Zhang Y, Cui H (April 2015). "HDAC9 promotes glioblastoma growth via TAZ-mediated EGFR pathway activation". Oncotarget. 6 (10): 7644–7656. doi:10.18632/oncotarget.3223. PMC 4480706. PMID 25760078.
13. Shimbo H, Oyoshi T, Kurosawa K (January 2018). "Contiguous gene deletion neighboring TWIST1 identified in a patient with Saethre-Chotzen syndrome associated with neurodevelopmental delay: Possible contribution of HDAC9". Congenital Anomalies. 58 (1): 33–35. doi:10.1111/cga.12216. PMID 28220539. S2CID 44464369.
14. Méjat A, Ramond F, Bassel-Duby R, Khochbin S, Olson EN, Schaeffer L (March 2005). "Histone deacetylase 9 couples neuronal activity to muscle chromatin acetylation and gene expression". Nature Neuroscience. 8 (3): 313–321. doi:10.1038/nn1408. PMID 15711539. S2CID 9965030.
15. Asare Y, Campbell-James TA, Bokov Y, Yu LL, Prestel M, El Bounkari O, et al. (August 2020). "Histone Deacetylase 9 Activates IKK to Regulate Atherosclerotic Plaque Vulnerability". Circulation Research. 127 (6): 811–823. doi:10.1161/CIRCRESAHA.120.316743. PMID 32546048. S2CID 219726725.
16. 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". Molecular and Cellular Biology. 22 (20): 7302–7312. doi:10.1128/mcb.22.20.7302-7312.2002. PMC 139799. PMID 12242305.
17. Petrie K, Guidez F, Howell L, Healy L, Waxman S, Greaves M, Zelent A (May 2003). "The histone deacetylase 9 gene encodes multiple protein isoforms". The Journal of Biological Chemistry. 278 (18): 16059–16072. doi:10.1074/jbc.M212935200. PMID 12590135.
18. Zhou X, Richon VM, Rifkind RA, Marks PA (February 2000). "Identification of a transcriptional repressor related to the noncatalytic domain of histone deacetylases 4 and 5". Proceedings of the National Academy of Sciences of the United States of America. 97 (3): 1056–1061. Bibcode:2000PNAS...97.1056Z. doi:10.1073/pnas.97.3.1056. PMC 15519. PMID 10655483.
19. Micheli L, D'Andrea G, Leonardi L, Tirone F (July 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. doi:10.1002/jcp.25467. PMID 27333946. S2CID 4070837.
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". The EMBO Journal. 18 (18): 5099–5107. doi:10.1093/emboj/18.18.5099. PMC 1171580. PMID 10487761.
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". The Journal of Biological Chemistry. 275 (20): 15594–15599. doi:10.1074/jbc.M908437199. PMID 10748098. S2CID 39220205.
22. Koipally J, Georgopoulos K (June 2002). "Ikaros-CtIP interactions do not require C-terminal binding protein and participate in a deacetylase-independent mode of repression". The Journal of Biological Chemistry. 277 (26): 23143–23149. doi:10.1074/jbc.M202079200. PMID 11959865.

Further reading

• Marks PA, Richon VM, Rifkind RA (August 2000). "Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells". Journal of the National Cancer Institute. 92 (15): 1210–1216. doi:10.1093/jnci/92.15.1210. PMID 10922406.
• Verdin E, Dequiedt F, Kasler HG (May 2003). "Class II histone deacetylases: versatile regulators". Trends in Genetics. 19 (5): 286–293. doi:10.1016/S0168-9525(03)00073-8. hdl:2268/80861. PMID 12711221.
• Sanger Centre, The; Washington University Genome Sequencing Cente, The (November 1998). "Toward a complete human genome sequence". Genome Research. 8 (11): 1097–1108. doi:10.1101/gr.8.11.1097. PMID 9847074.
• Nagase T, Ishikawa K, Suyama M, Kikuno R, Miyajima N, Tanaka A, et al. (October 1998). "Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro". DNA Research. 5 (5): 277–286. doi:10.1093/dnares/5.5.277. PMID 9872452.
• Miska EA, Karlsson C, Langley E, Nielsen SJ, Pines J, Kouzarides T (September 1999). "HDAC4 deacetylase associates with and represses the MEF2 transcription factor". The EMBO Journal. 18 (18): 5099–5107. doi:10.1093/emboj/18.18.5099. PMC 1171580. PMID 10487761.
• Zhou X, Richon VM, Rifkind RA, Marks PA (February 2000). "Identification of a transcriptional repressor related to the noncatalytic domain of histone deacetylases 4 and 5". Proceedings of the National Academy of Sciences of the United States of America. 97 (3): 1056–1061. Bibcode:2000PNAS...97.1056Z. doi:10.1073/pnas.97.3.1056. PMC 15519. PMID 10655483.
• Youn HD, Grozinger CM, Liu JO (July 2000). "Calcium regulates transcriptional repression of myocyte enhancer factor 2 by histone deacetylase 4". The Journal of Biological Chemistry. 275 (29): 22563–22567. doi:10.1074/jbc.C000304200. PMID 10825153.
• Zhang CL, McKinsey TA, Lu JR, Olson EN (January 2001). "Association of COOH-terminal-binding protein (CtBP) and MEF2-interacting transcription repressor (MITR) contributes to transcriptional repression of the MEF2 transcription factor". The Journal of Biological Chemistry. 276 (1): 35–39. doi:10.1074/jbc.M007364200. PMID 11022042.
• 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". The Journal of Biological Chemistry. 276 (38): 35826–35835. doi:10.1074/jbc.M104935200. PMID 11466315.
• Zhou X, Marks PA, Rifkind RA, Richon VM (September 2001). "Cloning and characterization of a histone deacetylase, HDAC9". Proceedings of the National Academy of Sciences of the United States of America. 98 (19): 10572–10577. Bibcode:2001PNAS...9810572Z. doi:10.1073/pnas.191375098. PMC 58507. PMID 11535832.
• Koipally J, Georgopoulos K (June 2002). "Ikaros-CtIP interactions do not require C-terminal binding protein and participate in a deacetylase-independent mode of repression". The Journal of Biological Chemistry. 277 (26): 23143–23149. doi:10.1074/jbc.M202079200. PMID 11959865.
• Kirsh O, Seeler JS, Pichler A, Gast A, Müller S, Miska E, et al. (June 2002). "The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase". The EMBO Journal. 21 (11): 2682–2691. doi:10.1093/emboj/21.11.2682. PMC 125385. PMID 12032081.
• Mahlknecht U, Schnittger S, Will J, Cicek N, Hoelzer D (April 2002). "Chromosomal organization and localization of the human histone deacetylase 9 gene (HDAC9)". Biochemical and Biophysical Research Communications. 293 (1): 182–191. doi:10.1016/S0006-291X(02)00193-6. PMID 12054582.
• 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". Molecular and Cellular Biology. 22 (20): 7302–7312. doi:10.1128/MCB.22.20.7302-7312.2002. PMC 139799. PMID 12242305.
• Hoogeveen AT, Rossetti S, Stoyanova V, Schonkeren J, Fenaroli A, Schiaffonati L, et al. (September 2002). "The transcriptional corepressor MTG16a contains a novel nucleolar targeting sequence deranged in t (16; 21)-positive myeloid malignancies". Oncogene. 21 (43): 6703–6712. doi:10.1038/sj.onc.1205882. PMID 12242670.
• Petrie K, Guidez F, Howell L, Healy L, Waxman S, Greaves M, Zelent A (May 2003). "The histone deacetylase 9 gene encodes multiple protein isoforms". The Journal of Biological Chemistry. 278 (18): 16059–16072. doi:10.1074/jbc.M212935200. PMID 12590135.

External links

• HDAC9+protein,+human at the U.S. 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.