Biology:HDAC9

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Histone deacetylase 9 is an enzyme that in humans is encoded by the HDAC9 gene.[1][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 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.[3]

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.[4]

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.[5]

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.[6] 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).[7]

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.[7]

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.[8]

Saethre-Chotzen syndrome

HDAC9 was suggested to contribute to developmental delay in Saethre-Chotzen syndrome (SCS) patients with 7p21 mirodeletions.[9]

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.[10]

Interactions

HDAC9 has been shown to interact with:


See also

References

  1. ↑ "HDAC4, a human histone deacetylase related to yeast HDA1, is a transcriptional corepressor". Molecular and Cellular Biology 19 (11): 7816–7827. November 1999. doi:10.1128/mcb.19.11.7816. PMID 10523670. 
  2. ↑ "MEF-2 function is modified by a novel co-repressor, MITR". The EMBO Journal 18 (18): 5085–5098. September 1999. doi:10.1093/emboj/18.18.5085. PMID 10487760. 
  3. ↑ 3.0 3.1 "Entrez Gene: HDAC9 histone deacetylase 9". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9734. 
  4. ↑ "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. August 2021. doi:10.1080/1061186X.2021.1878365. PMID 33480300. 
  5. ↑ "Associations among Genetic Variants and Intracranial Aneurysm in a Chinese Population". Yonsei Medical Journal 60 (7): 651–658. July 2019. doi:10.3349/ymj.2019.60.7.651. PMID 31250579. 
  6. ↑ "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. August 2022. doi:10.1007/s12035-022-02840-4. PMID 35927544. 
  7. ↑ 7.0 7.1 "HDAC9 Silencing Exerts Neuroprotection Against Ischemic Brain Injury via miR-20a-Dependent Downregulation of NeuroD1". Frontiers in Cellular Neuroscience 14: 544285. 2020. doi:10.3389/fncel.2020.544285. PMID 33584204. 
  8. ↑ "HDAC9 promotes glioblastoma growth via TAZ-mediated EGFR pathway activation". Oncotarget 6 (10): 7644–7656. April 2015. doi:10.18632/oncotarget.3223. PMID 25760078. 
  9. ↑ "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. January 2018. doi:10.1111/cga.12216. PMID 28220539. 
  10. ↑ "Histone deacetylase 9 couples neuronal activity to muscle chromatin acetylation and gene expression". Nature Neuroscience 8 (3): 313–321. March 2005. doi:10.1038/nn1408. PMID 15711539. 
  11. ↑ 11.0 11.1 "Histone Deacetylase 9 Activates IKK to Regulate Atherosclerotic Plaque Vulnerability". Circulation Research 127 (6): 811–823. August 2020. doi:10.1161/CIRCRESAHA.120.316743. PMID 32546048. 
  12. ↑ 12.0 12.1 "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. October 2002. doi:10.1128/mcb.22.20.7302-7312.2002. PMID 12242305. 
  13. ↑ 13.0 13.1 13.2 "The histone deacetylase 9 gene encodes multiple protein isoforms". The Journal of Biological Chemistry 278 (18): 16059–16072. May 2003. doi:10.1074/jbc.M212935200. PMID 12590135. 
  14. ↑ "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. February 2000. doi:10.1073/pnas.97.3.1056. PMID 10655483. Bibcode: 2000PNAS...97.1056Z. 
  15. ↑ "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. July 2017. doi:10.1002/jcp.25467. PMID 27333946. 
  16. ↑ "HDAC4 deacetylase associates with and represses the MEF2 transcription factor". The EMBO Journal 18 (18): 5099–5107. September 1999. doi:10.1093/emboj/18.18.5099. PMID 10487761. 
  17. ↑ "mHDA1/HDAC5 histone deacetylase interacts with and represses MEF2A transcriptional activity". The Journal of Biological Chemistry 275 (20): 15594–15599. May 2000. doi:10.1074/jbc.M908437199. PMID 10748098. 
  18. ↑ "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. June 2002. doi:10.1074/jbc.M202079200. PMID 11959865. 

Further reading

External links

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



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