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Histone deacetylase inhibitors reverse gene silencing in friedreich's ataxia

Academic Article
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Overview

authors

  • Herman, D.
  • Jenssen, K.
  • Burnett, R.
  • Soragni, E.
  • Perlman, S. L.
  • Gottesfeld, Joel

publication date

  • October 2006

journal

  • Nature Chemical Biology  Journal

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.

subject areas

  • Acetylation
  • Alleles
  • Anilides
  • Cell Line
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors
  • Friedreich Ataxia
  • Gene Expression Regulation
  • Gene Silencing
  • HeLa Cells
  • Heterochromatin
  • Histone Deacetylase Inhibitors
  • Histones
  • Humans
  • Iron-Binding Proteins
  • Molecular Structure
  • RNA, Messenger
  • Transcription, Genetic
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Identity

International Standard Serial Number (ISSN)

  • 1552-4450

Digital Object Identifier (DOI)

  • 10.1038/nchembio815

PubMed ID

  • 16921367
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Additional Document Info

start page

  • 551

end page

  • 558

volume

  • 2

issue

  • 10

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