Expansion of GAA·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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This work was supported by grants from the US National Institutes of Health (R21 NS048989) and the Friedreich's Ataxia Research Alliance (FARA). We thank FARA for postdoctoral support to D.H., R.B. and E.S., and M. Houser for overseeing blood donations at Scripps Clinic in La Jolla, California, USA. We also thank G. Joyce for providing facilities for chemical synthesis.
J.M.G. is a consultant to Repligen Corporation. Repligen has licensed compounds discussed in this paper from the Scripps Research Institute for therapeutics for Friedreich's ataxia and other related neurodegenerative and neuromuscular diseases.
*Note: In the version of this article initially published, no competing financial interests were declared. The authors now declare that they have competing interests that might be perceived to influence the results and discussion reported in this paper. The error has been corrected in the HTML and PDF versions of the article.
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Herman, D., Jenssen, K., Burnett, R. et al. Histone deacetylase inhibitors reverse gene silencing in Friedreich's ataxia. Nat Chem Biol 2, 551–558 (2006). https://doi.org/10.1038/nchembio815
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