Abstract
In recent years, it has become widely recognized that a comprehensive understanding of chromatin biology is necessary to better appreciate its role in a wide range of diseases. The histone code has developed as a new layer of our appreciation of transcription factor-based mechanisms of gene expression. Although epigenetic regulation refers to a host of chromatin modifications that occur at the level of DNA, histones, and histone-associated proteins, how this regulation is orchestrated is still incompletely understood. Of those processes that comprise the epigenetic regulatory machinery, DNA methylation and histone acetylation/deacetylation have been the most thoroughly studied. Compounds that act as inhibitors of DNA methyltransferases or histone deacetylases (HDACs) activate a variety of intracellular signaling pathways that ultimately affect the coordinated expression of multiple genes. The altered patterns of mRNA and protein expression collectively converge on pathways linked to apoptosis and cell cycle arrest, among others. This has prompted a widespread search for epigenetic inhibitors that could be used as chemotherapeutic agents, and several are undergoing clinical evaluation. More recently, there has been interest in the use of HDAC inhibitors to activate the expression of mRNAs that are down-regulated in various neurological and psychiatric conditions. Considerably less is known regarding the effect these drugs have on postmitotic cells such as neurons. Before we consider the clinical use of additional HDAC inhibitors to treat schizophrenia or unipolar depression, there are a number of key issues that need to be resolved.
Footnotes
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.109.061333
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ABBREVIATIONS:
- BDNF
- brain-derived neurotrophic factor
- SMA
- spinal muscular atrophy
- GAD67
- glutamic acid decarboxylase 67
- HAT
- histone acetyltransferase
- HDAC
- histone deacetylase
- MS-275
- N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl) aminomethyl]benzamide
- M344
- 4-(diethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide
- SIRT
- sirtuin, silent mating-type information regulation 2 homolog
- VPA
- valproic acid
- TSA
- trichostatin A
- CI-994
- tacedinaline, 4-acetamido-N-(2-aminophenyl)benzamide
- SAHA
- N-hydroxy-N′-phenyl-octanediamide
- FK228
- romidepsin
- PXD-101
- belinostat
- LBH589
- panobiostat
- NVP-LAQ824
- dacinostat.
- Received September 28, 2009.
- Accepted November 16, 2009.
- Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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