Histone deacetylase inhibitors reverse gene silencing in Friedreich's ataxia

Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Nature Chemical Biology (Impact Factor: 13.22). 11/2006; 2(10):551-8. DOI: 10.1038/nchembio815
Source: PubMed

ABSTRACT Expansion of GAA x TTC triplets within an intron in FXN (the gene encoding frataxin) leads to transcription silencing, forming the molecular basis for the neurodegenerative disease Friedreich's ataxia. Gene silencing at expanded FXN alleles is accompanied by hypoacetylation of histones H3 and H4 and trimethylation of histone H3 at Lys9, observations that are consistent with a heterochromatin-mediated repression mechanism. We describe the synthesis and characterization of a class of histone deacetylase (HDAC) inhibitors that reverse FXN silencing in primary lymphocytes from individuals with Friedreich's ataxia. We show that these molecules directly affect the histones associated with FXN, increasing acetylation at particular lysine residues on histones H3 and H4 (H3K14, H4K5 and H4K12). This class of HDAC inhibitors may yield therapeutics for Friedreich's ataxia.

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Available from: Ryan Burnett, Feb 20, 2015
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    • "Very little work has been done regarding the role of HDACs in neurologic disorders; however, a few studies show great promise. HDACs have been proposed as a target against the autosomal recessive neurodegenerative disorder Friedreich ataxia (FRDA) (Herman et al., 2006), a disease predominantly caused by a homozygous GAA repeat expansion within the FXN gene that result in a frataxin protein deficit. This deficit is due to epigenetic changes and heterochromatin-mediated gene silencing (Al-Mahdawi et al., 2008; De Biase et al., 2009). "
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    ABSTRACT: Modulation of gene expression is a constant and necessary event for mammalian brain function. An important way of regulating gene expression is through the remodeling of chromatin, the complex of DNA and histone proteins around which DNA wraps. The “histone code hypothesis” places histone post-translational modifications as a significant part of chromatin remodeling to regulate transcriptional activity. Acetylation of histones by histone acetyl transferases and deacetylation by histone deacetylases (HDACs) at lysine residues are the most studied histone post-translational modifications in cognition and neuropsychiatric diseases. Here, we review the literature regarding the role of HDACs in brain function. Among the roles of HDACs in the brain, studies show that they participate in glial lineage development, learning and memory, neuropsychiatric diseases, and even rare neurologic diseases. Most HDACs can be targeted with small molecules. However, additional brain-penetrant specific inhibitors with high central nervous system exposure are needed to determine the cause-and-effect relationship between individual HDACs and brain-associated diseases.
    01/2015; 1(1):20-27. DOI:10.1016/j.nepig.2014.10.002
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    • "HDAC inhibitors appeared as appealing candidates to prevent deacetylation of histones, and thus open the chromatin to increase frataxin gene transcription. A first screening of commercially available HDAC inhibitors was performed on FRDA patient and control lymphoblastoid cells, allowing the identification and the optimization of a promising compound able to increase both frataxin mRNA and protein levels in patient cells (Herman et al. 2006). After additional developments, several derivatives were tested on KIKI mice in short-term studies, confirming their ability to temporarily reverse frataxin gene silencing (Rai et al. 2008, 2010). "
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    ABSTRACT: The development and use of animal and cellular models of Friedreich ataxia (FRDA) are essential requirements for the understanding of FRDA disease mechanisms and the investigation of potential FRDA therapeutic strategies. Although animal and cellular models of lower organisms have provided valuable information on certain aspects of FRDA disease and therapy, it is intuitive that the most useful models are those of mammals and mammalian cells, which are the closest in physiological terms to FRDA patients. To date, there have been considerable efforts put into the development of several different FRDA mouse models and relevant FRDA mouse and human cell line systems. We summarize the principal mammalian FRDA models, discuss the pros and cons of each system, and describe the ways in which such models have been used to address two of the fundamental, as yet unanswered, questions regarding FRDA. Namely, what is the exact pathophysiology of FRDA and what is the detailed genetic and epigenetic basis of FRDA?
    Journal of Neurochemistry 08/2013; 126(s1). DOI:10.1111/jnc.12219 · 4.24 Impact Factor
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    • "While the previous therapeutic approaches for FRDA mostly address the consequences of Frataxin deficiency, a more radical strategy is emerging to antagonise the aberrant silencing of the FXN gene. One of the encouraging outcomes is the development of HDAC inhibitors for creating a more accessible chromatin by reducing histone deacetylation and thereby subsequent methylation (Festenstein 2006; Herman et al. 2006; Gottesfeld 2007; Rai et al. 2010; Sandi et al. 2011). Results so far seem promising in terms of up-regulating FXN in FRDA (Gottesfeld et al. 2013). "
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    ABSTRACT: This is an exciting time in the study of Friedreich's ataxia. Over the last 10 years much progress has been made in uncovering the mechanisms, whereby the Frataxin gene is silenced by (GAA)n repeat expansions and several of the findings are now ripe for testing in the clinic. The discovery that the Frataxin gene is heterochromatinised and that this can be antagonised in vivo has led to the tantalizing possibility that the disease might be amenable to a more radical therapeutic approach involving epigenetic modifiers. Here, we set out to review progress in the understanding of the fundamental mechanisms whereby genes are regulated at this level and how these findings have been applied to achieve a deeper understanding of the dysregulation that occurs as the primary genetic lesion in Friedreich's ataxia.
    Journal of Neurochemistry 08/2013; 126(s1). DOI:10.1111/jnc.12254 · 4.24 Impact Factor
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