HDAC Inhibitors Disease Mechanism VI: Changes in Gene Transcription
Drugs Able to Affect Gene Transcription
Drug Summary: Drugs known as HDAC inhibitors have been found to increase survival rates in fruit-fly models of Huntington’s disease. HDAC inhibitors interfere with the regulation of gene expression by inhibiting the activity of enzymes known as histone deacetylases.
Histone deacetylase (HDAC) inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA) inhibit the activity of the enzymes known as histone deacetylases. Inhibiting the activity of histone deacetylases has been reported to have beneficial effects on fruit-fly models of HD. What are histone deacetylases and why are they significant in the study of HD? To answer these questions, we will explore histones and their role in gene expression, learn about certain histone-affecting enzymes, and then address how regulation of these enzymes can have potentially beneficial effects for an HD patient.
Histones and DNA
Histones are proteins that play a part in the regulation of transcription by helping to condense DNA into its compact form as chromosomes. (For more information on chromosomes, click here.) Transcription is one of the steps involved in the production of proteins from DNA. In order for transcription to occur, molecules known as transcription factors have to bind to specific binding sites on the DNA. When the DNA molecule is in its compact form, it is often difficult for other proteins to access it and because of this, transcription occurs infrequently. By ensuring that the DNA is bundled up into chromosomes, histones play a major role in restricting the binding of transcription factors to the DNA molecule.
The binding of histones to DNA is controlled by various enzymes present in the cell. When a certain gene in the DNA needs to be transcribed, enzymes known as histone acetyltransferases add an acetyl group (a chemical group) to the histone proteins, releasing the restricted access to the DNA imposed by the histones. Once access to the DNA is no longer restricted, transcription factors can bind to the DNA and activate gene transcription. When the gene no longer needs to be transcribed, enzymes known as histone deacetylases (HDAC) remove the acetyl group added by the histone acetyltransferases. The removal of the chemical group enables histones to bind to the DNA, once again restricting access to the DNA. In review, histone acetyltransferases allow transcription to occur, HDACs prevent transcription, and HDAC inhibitors reverse these effects, allowing transcription to occur.
Cells affected by HD are thought to exhibit abnormal gene expression due to insufficient transcription of certain genes. It is thought that HDAC inhibitors might counteract this effect by physically allowing transcription factors to bind to the DNA.
In some nerve cells affected with HD, abnormal gene expression occurs when some transcription factors and coactivators are not available to do their job. Coactivators are molecules that help the transcription factors bind to the DNA in order for gene transcription to occur. What happened to these coactivators and transcription factors? In order to answer this question, we need to review some of the disease mechanisms that take place in the HD cell.
A brief review of HD mechanisms
The expanded CAG repeat found in the huntington gene of people with HD leads to the production of an altered form of the the huntingtin protein. At some point in the life of this altered protein, enzymes known as caspases cleave the protein at various sites, resulting in the production of huntingtin fragments. These fragments end up being transported into the nucleus of the HD nerve cell where they aggregate to form neuronal inclusions (NIs). Figure 3 shows a diagram depicting the formation of NIs from the altered huntingtin protein. For more information about altered huntingtin protein and protein aggregation, click here.
Recent studies have shown that the NIs “trap” various coactivators and transcription factors by coaggregating with the coactivators, preventing the transcription factors from doing their job. Figure 4 shows a diagram illustrating the process of transcription and the effects of NI formation on transcription.
The discovery that NIs trap coactivators and transcription factors led scientists to speculate that one of the ways by which HD progresses is through the loss of transcription of several key genes essential for cell survival. It was then important for scientists to try to find out what molecules are being trapped by the NIs, in order to think of ways on how to counter this molecular “trapping.” We will now go over some of the specific molecules that scientists believe are trapped by the NIs and how HDAC inhibitors might counteract this trapping.
Molecules trapped by NIs
A few years ago, it was reported that the coactivator CREB-binding protein (CBP) coaggregates with neuronal inclusions. CBP acts as a coactivator through its role as a histone acetyltransferase enzyme, allowing certain transcription factors to bind to DNA. Because CBP is trapped by the NIs, these transcription factors are no longer able to bind to the DNA and certain genes are not transcribed.
How the trapping of CBP leads to cell death
P53 is one of the transcription factors that requires the presence of CBP in order to bind to DNA. p53 is better known for its role as a tumor-suppressor protein, but it is also involved in the regulation of nerve cellapoptosis. When few CBP molecules are available in the cell to coactivate p53, it is unable to access and bind to the DNA. Without p53, abnormal gene transcription and expression occurs, and scientists speculate that this error in transcription may lead to cell death.
In summary, the altered huntingtin protein forms NIs that trap coactivators such as CBP. Loss of CBP results in the loss of histone acetylation, which in turn results in the inability of the transcription factor p53 to bind to DNA. Drugs such as HDAC inhibitors that could compensate for the loss of the coactivator CBP could, in theory, be possible treatments for HD. The following section summarizes some of the recent studies that test this theory using animal models.
Research on drugs involved in CBP and transcription
Steffan, et al. (2001) looked into the possibility of reversing the effects of CBP coaggregation with nuclear inclusions. Because CBP functions as a histone acetyltransferase, scientists hypothesized that inhibiting the function of histone deacetylases (HDAC) might compensate for the loss of histone acetyltransferases. The reduction in deacetylase activity should compensate for the loss of acetyltransferase activity. In other words, blocking the inhibitor of transcription would, on the average, make up for the low levels of transcription activators.
To test this idea, Steffan, et al. turned their attention to a Drosophila (fruit fly) model of HD. These fruit flies were genetically modified to express an altered huntingtin protein. Preliminary testing revealed degeneration of nerve cells and decreased survival rates in the flies similar to what is observed in people with HD. To assess the efficacy of HDAC inhibitors, the scientists measured the differences in survival rates of treated and untreated flies.
The flies were fed with food containing various HDAC inhibitors. The inhibitors tested included sodium butyrate and suberoylanilide hydroxamic acid (SAHA). After treatment, the researchers discovered that the flies fed with SAHA showed increased histone acetylation and increased survival rates. 70% of untreated flies showed early death compared to 45% of SAHA-treated flies. When flies already experiencing neurodegeneration were treated with SAHA, researchers observed a slowing of further neurodegeneration.
The results of the study suggest that the altered huntingtin protein does reduce levels of acetylation and transcription by sequestering coactivators (such as CBP and others) and trapping them into aggregates. The use of histone-deacetylase inhibitors had remarkable effects in this fruit fly model of HD. Several such inhibitors, including SAHA, are approved by the FDA and are already in clinical use or in early clinical trials.
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-E. Tan, 11-21-01
For further reading:
Steffan, et al. "Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila". 2001. Nature 413: 739-743. Treatment with HDAC inhibitors increased survival rates in a Drosophila model of HD.
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The expanded CAG repeat found in the huntington gene of people with HD leads to the production of an altered form of the the huntingtin protein. At some point in the life of this altered protein, enzymes known as 
Recent studies have shown that the NIs “trap” various coactivators and transcription factors by coaggregating with the coactivators, preventing the transcription factors from doing their job. Figure 4 shows a diagram illustrating the process of transcription and the effects of NI formation on transcription.
In summary, the altered huntingtin protein forms NIs that trap coactivators such as CBP. Loss of CBP results in the loss of histone acetylation, which in turn results in the inability of the transcription factor p53 to bind to DNA. Drugs such as HDAC inhibitors that could compensate for the loss of the coactivator CBP could, in theory, be possible treatments for HD. The following section summarizes some of the recent studies that test this theory using animal models.
