Herman, D. et al. Histone deacetylase inhibitors reverse gene silencing in Friedreich's ataxia. Nat. Chem. Biol. 2, 551-558

Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Nature Chemical Biology (Impact Factor: 13). 11/2006; 2(10):551-8. DOI: 10.1038/nchembio815
Source: PubMed


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.

Download full-text


Available from: Ryan Burnett, Feb 20, 2015
    • "In the case of FRDA the repeat unit is GAA/TTC and the repeat tract is located in the first intron of the frataxin (FXN) gene, a gene situated at 9q21.1. Expansion results in epigenetic modifications that downregulate the transcription of affected alleles [1] [2] [3] [4] [5]. The result of this downregulation is a progressive neurodegeneration that leads to gait and balance difficulties that often results in patients becoming wheelchair-bound at an early age. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Friedreich ataxia (FRDA) is a member of the Repeat Expansion Diseases, a group of genetic conditions resulting from an increase/expansion in the size of a specific tandem array. FRDA results from expansion of a GAA/TTC-tract in the first intron of the frataxin gene (FXN). The disease-associated tandem repeats all form secondary structures that are thought to contribute to the propensity of the repeat to expand. The subset of these diseases that result from a CGG/CCG-repeat expansion, such as Fragile X syndrome, also express a folate-sensitive fragile site coincident with the repeat on the affected chromosome. This chromosome fragility involves the generation of chromosome/chromatid gaps or breaks, or the high frequency loss of one or both copies of the affected gene when cells are grown under folate stress or as we showed previously, in the presence of an inhibitor of the ATM checkpoint kinase. Whether Repeat Expansion Disease loci containing different repeats form similar fragile sites was not known. We show here that the region of chromosome 9 that contains the FXN locus is intrinsically prone to breakage in vivo even in control cells. However, like FXS alleles, FRDA alleles show significantly elevated levels of chromosome abnormalities in the presence of an ATM inhibitor, consistent with the formation of a fragile site.
    No preview · Article · Sep 2015
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Jan 2015
  • Source
    • "Expanded intronic GAA repeats can also cause abnormal heterochromatinization [19], [20] that subsequently leads to frataxin gene silencing. This is supported by the observation that the hallmarks of heterochromatin such as DNA methylation [21]–[24], histone deacetylation [25], [26] and methylation of histone H3 lysine 9 [27], [28] exist abundantly in the intronic GAA repeats-containing region of the frataxin gene. Thus, GAA repeat expansion can result in frataxin gene silencing, leading to a deficiency of frataxin by directly interfering with its gene transcription and/or facilitating the formation of heterochromatin at the region near the promoter of the frataxin gene. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Expansion of GAA·TTC repeats within the first intron of the frataxin gene is the cause of Friedreich's ataxia (FRDA), an autosomal recessive neurodegenerative disorder. However, no effective treatment for the disease has been developed as yet. In this study, we explored a possibility of shortening expanded GAA repeats associated with FRDA through chemotherapeutically-induced DNA base lesions and subsequent base excision repair (BER). We provide the first evidence that alkylated DNA damage induced by temozolomide, a chemotherapeutic DNA damaging agent can induce massive GAA repeat contractions/deletions, but only limited expansions in FRDA patient lymphoblasts. We showed that temozolomide-induced GAA repeat instability was mediated by BER. Further characterization of BER of an abasic site in the context of (GAA)20 repeats indicates that the lesion mainly resulted in a large deletion of 8 repeats along with small expansions. This was because temozolomide-induced single-stranded breaks initially led to DNA slippage and the formation of a small GAA repeat loop in the upstream region of the damaged strand and a small TTC loop on the template strand. This allowed limited pol β DNA synthesis and the formation of a short 5'-GAA repeat flap that was cleaved by FEN1, thereby leading to small repeat expansions. At a later stage of BER, the small template loop expanded into a large template loop that resulted in the formation of a long 5'-GAA repeat flap. Pol β then performed limited DNA synthesis to bypass the loop, and FEN1 removed the long repeat flap ultimately causing a large repeat deletion. Our study indicates that chemotherapeutically-induced alkylated DNA damage can induce large contractions/deletions of expanded GAA repeats through BER in FRDA patient cells. This further suggests the potential of developing chemotherapeutic alkylating agents to shorten expanded GAA repeats for treatment of FRDA.
    Full-text · Article · Apr 2014 · PLoS ONE
Show more