Distribution of histone deacetylases 1–11 in the rat brain
Although protein phosphorylation has been characterized more extensively, modulation of the acetylation state of signaling molecules is now being recognized as a key means of signal transduction. The enzymes responsible for mediating these changes include histone acetyl transferases and histone deacetylases (HDACs). Members of the HDAC family of enzymes have been identified as potential therapeutic targets for diseases ranging from cancer to ischemia and neurode generation. We initiated a project to conduct comprehensive gene expression mapping of the 11 HDAC isoforms (HDAC1-11) (classes I, II, and IV) throughout the rat brain using high-resolution in situ hybridization (ISH) and imaging technology. Internal and external data bases were employed to identify the appropriate rat sequence information for probe selection. In addition, immunohistochemistry was performed on these samples to separately examine HDAC expression in neurons, astrocytes, oligodendrocytes, and endothelial cells in the CNS. This double-labeling approach enabled the identification of specific cell types in which the individual HDACs were expressed. The signals obtained by ISH were compared to radiolabeled standards and thereby enabled semiquantitative analysis of individual HDAC isoforms and defined relative levels of gene expression in >50 brain regions. This project produced an extensive atlas of 11 HDAC isoforms throughout the rat brain, including cell type localization, providing a valuable resource for examining the roles of specific HDACs in the brain and the development of future modulators of HDAC activity.
Index EntriesHistone deacetylase gene expression brain transcription
Acharya M. R., Sparreboom, A., Venitz J., and Figg W. D. (2005) Rational development of histone deacetylase inhibitors as anticancer agents: a review. Mol. Pharmacol.
, 917–932.PubMedCrossRefGoogle Scholar
Ajamian F., Suuronen T., Salminen A., and Reeben M. (2003) Upregulation of class II histone deacetylases mRNA during neural differentiation of cultured rat hippocampal progenitor cells. neurosci. Lett.
, 57–60.PubMedCrossRefGoogle Scholar
Alarcon J. M., Malleret G., Touzani K., et al. (2004) Chromatin acetylation memory, and LTP are impaired in CBP+/−mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Neuron
, 947–959.PubMedCrossRefGoogle Scholar
Araki T., Sasaki Y., and Milbrandt J. (2004) Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science
, 1010–1013.PubMedCrossRefGoogle Scholar
Bereshchenko O. R., Gu W., and Dalla-Favera R. (2002) Acetylation inactivates the transcriptional repressor BCL6. Nat. Genet.
, 606–613.PubMedCrossRefGoogle Scholar
Bolger T. A. and Yao T. P. (2005) Intracellular trafficking of histone deacetylase 4 regulates neuronal cell death. J. Neurosci.
, 9544–9553.PubMedCrossRefGoogle Scholar
Bradbury C. A., Khanim G. L., Hayden R., et al. (2005). Histone deacetylase in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors. Leukemia
, 1751–1759.PubMedCrossRefGoogle Scholar
Broide R. S., Trembleau A., Ellison J. A., et al. (2004) Standardized quantitative in situ hybridization using radioactive oligonucleotide probes for detecting relative levels of mRNA transcripts verified by real-time PCR. Brain Res.
Camelo S., Iglesias A. H., Hwang D., et al. (2005) Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis. J Neuroimmunol.
, 10–21.PubMedCrossRefGoogle Scholar
Chiurazzi P., Pomponi M. G., Pietrobono R., Bakker C. E., Neri G., and Oostra B. A. (1999) Synergistic effect of histone hyperacetylation and DNA demethylation in the reactivation of the FMR1 gene. Hum. Mol. Genet.
, 2317–2323.PubMedCrossRefGoogle Scholar
Choi J. H., Oh S. W., Kang M. S., et al. (2001) Expression profile of histone deacetylase 1 in gastric cancer tissues. Jpn. J. Cancer Res.
, 1300–1304.PubMedGoogle Scholar
Choi J. H., Kwon H. J., Yoon B. I., et al. (2005) Trichostatin A attenuates airway inflammation in mouse asthma model. Clin. Exp. Allergy
, 89–96.PubMedCrossRefGoogle Scholar
Dokmanovic M. and Marks P. A. (2005) Prospects: histone deacetylase inhibitors. J. Cell. Biochem.
, 293–304.PubMedCrossRefGoogle Scholar
Emerich D. F., Skinner S. J., Borlongan C. V., Vasconcellos A. V., and Thanos C. G. (2005) The choroid plexus in the rise, fall and repair of the brain. Bioessays
, 262–274.PubMedCrossRefGoogle Scholar
Ferrante R. J., Kublius J. K., Lee J., et al. (2003) Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington's disease mice. J. Neurosci.
, 9418–9427.PubMedGoogle Scholar
Franklin K. B. J. and Paxinos G. (1997) The Mouse Brain in Stereotaxic Coordinates
, Academic Press, San Diego, CA.Google Scholar
Gao L., Cueto M. A., Asselbergs F., and Atadja P. (2002) Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family. J. Biol. Chem.
, 24,748–25,755.Google Scholar
Gardian G., Yang L., Cleren C., Calingasan N. Y., Klivenyi P., and Beal M. F. (2005) Neuroprotective effects of phenylbutyrate in the N171-82O transgenic mouse model of Huntington's disease. J. Biol. Chem.
, 556–563.PubMedGoogle Scholar
Gardian G., Browne S. E., Choi D. K., et al. (2004) Neuroprotective effects of phenylbutyrate against MPTP neurotoxicity. Neuromol. Med.
, 235–241.CrossRefGoogle Scholar
Gregoretti I. V., Lee Y. M., and Goodson H. V. (2004) Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J. Mol. Biol.
, 17–31.PubMedCrossRefGoogle Scholar
Haggarty S. J., Koeller K. M., Wong J. C., Grozinger C. M., and Schreiber, S. L. (2003) Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proc. Natl. Acad. Sci. U. S. A.
, 4389–4394.PubMedCrossRefGoogle Scholar
Hao Y., Creson T., Zhang L., et al. (2004) Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis. J. Neurosci.
, 6590–6599.PubMedCrossRefGoogle Scholar
Hockly E., Richon V. M., Woodman B., et al. (2003) Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc. Natl. Acad. Sci. U.S.A.
, 2041–2046.PubMedCrossRefGoogle Scholar
Hoshino M., Tagawa K., Okuda T., et al. (2003) Histone deacetylase activity is retained in primary neurons expressing mutant huntingtin protein. J. Neurochem.
, 257–267.PubMedCrossRefGoogle Scholar
Ito, K., Caramori G., Lim S., et al. (2002) Expression and activity of histone deacetylases in human asthmatic airways. Am. J. Respir. Crit. Care Med.
, 392–396.PubMedCrossRefGoogle Scholar
Ito K. K., Ito M., Elliott W. M., et al. (2005) Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N. Engl. J. Med.
, 1967–1976.PubMedCrossRefGoogle Scholar
Jeong M. R., Hashimoto, R., Senatorov V. V., et al. (2003) Valproic acid, a mood stabilizer and anticonvulsant, protects rat cerebral cortical neurons from spontaneous cell death: a role of histone deacetylase inhibition. FEBS Lett.
, 74–78.PubMedCrossRefGoogle Scholar
Johnstone R. W. (2002) Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat. Rev. Drug Discov.
, 287–299.PubMedCrossRefGoogle Scholar
Kawaguchi Y., Kovacs J. J., McLaruin A., Vance J. M., Ito, A., and Yao T. P. (2003) The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell
, 727–738.PubMedCrossRefGoogle Scholar
Kelly W. K., O'Connor O. A., Krug L. M., et al. (2005) Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J. Clin. Oncol.
, 3923–3931.PubMedCrossRefGoogle Scholar
Kouraklis G. and Theocharis S. (2002) Histone deacetylase inhibitors and anticancer therapy. Curr. Med. Chem. Anti-Cancer Agents
, 477–484.CrossRefGoogle Scholar
Langley B., Gensert J. M., Beal M. F., and Ratan R. R. (2005) Remodeling chromatin and stress resistance in the central nervous system: histone deacetylase inhibitors as noveland broadly effective neuroprotective agents. Curr. Drug Targets CNS Neurol. Disord.
, 41–50.PubMedCrossRefGoogle Scholar
Lin A. Y. (2005) Histone deacetylase activity and COPD, author reply. N. Engl. J. Med.
, 528, 529.PubMedCrossRefGoogle Scholar
Marks P. A., Miller T., and Richon V. M. (2003) Histone deacetylases. Curr. Opin. Pharmacol.
, 344–351.PubMedCrossRefGoogle Scholar
Marks P. A., Richon V. M., Miller T., and Kelley W. K. (2004) Histone deacetylase inhibitors. Adv. Cancer Res.
, 137–168.PubMedCrossRefGoogle Scholar
Moradei O., Maroun C. R., Paquin I., and Vaisburg A. (2005) Histone deacetylase inhibitors: latest developments, trends and prospects. Curr. Med. Chem. Anti-Cancer Agents
, 529–560.CrossRefGoogle Scholar
Naruse Y., Oh-hashi K., Iijima N., Naruse M., Yoshioka H., and Tanaka M. (2004) Circadian and light-induced transcription of clock gene Per1 depends on histone acetylation and deacetylation. Mol. Cell. Biol.
, 6278–6287.PubMedCrossRefGoogle Scholar
Panteleeva I., Rouaux C., Larmet Y., Boutillier S., Loeffler J. P., and Boutillier A. L. (2004) HDAC-3 participates in the repression of e2f-dependent gene transcription in primary differentiated neurons. Ann. N. Y. Acad. Sci.
, 656–660.PubMedCrossRefGoogle Scholar
Ren M., Leng Y., Jeong M., Leeds P. R., and Chuang D. M. (2004) Valproic acid reduces brain damage induced by transient focal cerebral ischemia in rats: potential roles of histone deacetylase inhibition and heat shock protein induction. J. Neurochem.
, 1358–1367.PubMedCrossRefGoogle Scholar
Richon V. M., Zhou X., Rifkind R. A., and Marks P. A. (2001) Histone deacetylase inhibitors: development of suberoylanilide hydroxamic acid (SAHA) for the treatment of cancers. Blood Cell Mol. Dis.
, 260–264.CrossRefGoogle Scholar
Robyr D., Suka Y., Xenarios I., et al. (2002) Microarray deacetylation maps determine genome-wide functions for yeast histone deacetylases Cell
, 437–446.PubMedCrossRefGoogle Scholar
Roth S.Y., Denu J. M., and Allis C. D. (2001) Histone acetyltransferases. Annu. Rev. Biochem.
, 81–120.PubMedCrossRefGoogle Scholar
Saha R. N. and Pahan K. (2005) HATs and HDACs in neurodegeneration: a tale of disconcerted acetylation homeostasis. Cell Death Differ
, 539–550.Google Scholar
Shabbeer S., and Carducci M. A. (2005) Focus on deacetylation for therapeutic benefit. Investigational Drugs
, 144–154.Google Scholar
Shen S., Li J., and Casaccia-Bonnefil P. (2005) Histone modifications affect timing of oligodendrocyte progenitor differentiation in the developing rat brain. J. Cell. Biol.
, 577–589.PubMedCrossRefGoogle Scholar
Vaghefi H., and Neet K. E. (2004) Deacetylation of p53 after nerve growth factor treatment in PC12 cells as a post-translational modification mechanism of neurotrophin-induced tumor suppressor activation. Oncogene
, 8078–8087.PubMedCrossRefGoogle Scholar
Voelter-Mahlknecht S., Ho A. D., and Mahlknecht, U. (2005) Chromosomal organization and locolization of the novel class IV human histone deacetylase 11 gene. Int. J. Mol. Med.
, 589–598.PubMedGoogle Scholar
Yamaguchi M., Tonou-Fujimori N., Komori A., et al. (2005) Histone deacetylase 1 regulates retinal neurogenesis in zebrafish by suppressing Wnt and Notch signaling pathways. Development
, 3027–3043.PubMedCrossRefGoogle Scholar
Yu X., Guo Z. S., Marcu M. G., et al. (2002) Modulation of p53, ErbB1, ErbB2, and Raf-1 expression in lung cancer cells by depsipeptide FR901228. J. Natl. Cancer Inst.
, 504–513.PubMedGoogle Scholar