In the ebb and flow of the genome, HATs are the ebb and HDACs are the flow. HDACs are responsible for removing the acetyl groups put on histones (and other proteins) by the histone acetyltransferases (HATs). This process is a vital aspect of epigenetic regulation of gene expression and more generally for the control of cellular stability.
Histone Deacetylase Classes
Higher organisms have a more complex set of HDACs. These HDACs have been divided into three classes based on sequence homology and phylogenetic relationship see (de Ruijter et al., 2003): class I is similar to Rpd3 and Hos1/2, class II is similar to Hos3 and HDA1 and class three is similar to the sirtuins. Higher eukaryotes also have an unrelated HDAC, in mammals HDAC11, which forms its own fourth class. Classes I and II share a conserved catalytic mechanism: they both use zinc to catalyze hydrolysis of the lysine-amino bond. Class IV has a similar mechanism, though it evolved separately. Class III are totally different, and rely on NAD onto which to transfer the acetyl group, thus making them important for energy metabolism as well as transcription (Blander and Guarente, 2004). Mammals have 18 known HDACs divided among these 4 classes (de Ruijter et al., 2003).
The regulation of HDACs is a very intricate and balanced process. Other than HDAC8, HDACs function as large, multi-protein complexes composed of several, often different HDACs (Yang and Seto, 2003). These complexes help to direct and coordinate HDAC function. Post-translational modifications are also crucial for HDAC function. Phosphorylation has been shown to be especially important for regulating class I HDACs. High phosphorylation of HDAC2 is required for its localization to promoters, while low phosphorylation causes its localization to gene bodies (Sun et al., 2007).
Given the core biological function of HDACs, it is not surprising that they are extremely important in disease and are the target of many drugs. Imbalance of histone acetylation is a common aspect of many disorders. HDAC inhibitors (HDACi’s) are common drugs for treating cancers, neurodegenerative diseases, and metabolic disorders to name a few (Tang et al., 2013). Since HDACs often act broadly on the transcription of many genes, their inhibition results downstream changes in gene-expression conferring their therapeutic properties (Kelly and Marks, 2005). HDACi’s have long been used in treating neurological conditions, but their use in cancer treatments is just heating up. Vorinostat is one two HDACi cancer treatment drugs on the market. It is used to treat cutaneous T cell lymphoma and functions by inhibiting class I and II HDACs leading to antiproliferative effects on gene expression (Kelly and Marks, 2005).
Recently, interest in HDACi’s as cognitive enhancers has taken root. It has been known for some time that increased histone acetylation in the brain is associated with memory formation, while decreased acetylation is associated with memory impairment (Federman et al., 2009; Stilling and Fischer, 2011). It was later shown that HDACi’s could rescue some cognitive-impairments to normal functioning (Fischer et al., 2010). Whether HDACi’s can actually enhance cognitive function above normal levels in normal individuals is a topic of current research.
Histone Deacetylase Additional Reading
Haberland, M., Montgomery, R.L., and Olson, E.N. (2009). The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat. Rev. Genet. 10, 32-42.
This review explores many of the basics of HDACs: regulation of their expression, classification, mechanistics. The authors then go over specific HDACs and the role of each in development and cellular function.
West, A.C., and Johnstone, R.W. (2014). New and emerging HDAC inhibitors for cancer treatment. J. Clin. Invest. 124, 30-39.
This recent review assess the two approved HDACi anti-cancer agents. The review also examines the function and potential of several other HDACi’s currently at various stages of development.
- Blander, G., and Guarente, L. (2004). The Sir2 family of protein deacetylases. Annu. Rev. Biochem. 73, 417-435.
- de Ruijter, A.J., van Gennip, A.H., Caron, H.N., Kemp, S., and van Kuilenburg, A.B. (2003). Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem. J. 370, 737-749.
- Federman, N., Fustinana, M.S., and Romano, A. (2009). Histone acetylation is recruited in consolidation as a molecular feature of stronger memories. Learn. Mem. 16, 600-606.
- Fischer, A., Sananbenesi, F., Mungenast, A., and Tsai, L.H. (2010). Targeting the correct HDAC(s) to treat cognitive disorders. Trends Pharmacol. Sci. 31, 605-617.
- Kelly, W.K., and Marks, P.A. (2005). Drug insight: Histone deacetylase inhibitors–development of the new targeted anticancer agent suberoylanilide hydroxamic acid. Nat. Clin. Pract. Oncol. 2, 150-157.
- Stilling, R.M., and Fischer, A. (2011). The role of histone acetylation in age-associated memory impairment and Alzheimer’s disease. Neurobiol. Learn. Mem. 96, 19-26.
- Sun, J.M., Chen, H.Y., and Davie, J.R. (2007). Differential distribution of unmodified and phosphorylated histone deacetylase 2 in chromatin. J. Biol. Chem. 282, 33227-33236.
- Tang, J., Yan, H., and Zhuang, S. (2013). Histone deacetylases as targets for treatment of multiple diseases. Clin. Sci. (Lond) 124, 651-662.
- Yang, X.J., and Seto, E. (2003). Collaborative spirit of histone deacetylases in regulating chromatin structure and gene expression. Curr. Opin. Genet. Dev. 13, 143-153.