The mechanism of FXN silencing by the expanded GAA repeat has been the object of intense investigation, mostly because its understanding may offer a target for treatment. Because of the presence of an intact frataxin coding sequence in affected individuals on at least 1 chromosome, by partially overcoming the silencing imposed by the expanded GAA repeat, we can expect that sufficient levels of FXN expression may be restored to block or slow down disease progression or even, if the intervention is made before symptoms appear, to prevent disease development. Considering that carriers are clinically normal, pushing FXN expression to about half of normal in affected individuals may be enough to avoid disease. Clues to the mechanism of FXN silencing came from studies on the DNA structure and properties of the GAA repeat and, more recently, studies on the structure of chromatin in the region of the repeat. Studies on DNA structure moved from the fact that the GAA-repeat DNA contains only purines (R, G, and A) in 1 strand and pyrimidines (Y, C, and T) in the complementary strand. Such R·Y sequences have been known for some time to adopt a peculiar structure called a triplex, at least in the test tube. Triplexes are 3-stranded nucleic acid structures in which a third strand occupies the major groove of the DNA double helix and is kept in place by a special type of base pair, called Hoogsteen pairs, with the bases in the double helix. In intramolecular triplexes, the R·Y DNA folds back onto itself to form the triple helix structure. Four different isomers may form: 2 based on R·R·Y structures, in which the R strand from 1 part of the sequence pairs with the double R·Y helix from another part of the sequence, leaving a single-stranded Y region; and 2 based on Y·R·Y structures, in which it is the Y strand that pairs with the double helix. Intermolecular triplexes are formed between oligonucleotides or polynucleotides (DNA or RNA) and target R·Y sequences on duplex DNA. R·R·Y triplexes are formed at a neutral pH by a GAA repeat as found in FRDA. Further investigations showed that an even more complicated structure, called sticky DNA, may be formed by such repeats.41 Sticky DNA consists of complexes formed by joining 2 DNA segments at the triplex region through the exchange of the third GAA-containing (R) strand. There is a clear correlation between the length of a GAA repeat, which confers the ability to form sticky DNA, and its pathogenicity in FRDA. The length threshold to form sticky DNA is about 59 repeats and the shortest reported pathologic allele in FRDA is 66 repeats. Furthermore, interruptions in the GAA repeat sequence prevent sticky DNA formation and are present in some rare long, nonpathogenic alleles of the FXN repeat. Sticky DNA is a strong inhibitor of transcription in vitro, as it impedes the progression of RNA polymerase, providing a possible direct mechanism for FXN silencing. However, in the eukaryotic nucleus, DNA is not free in solution, but it is associated with proteins, histones, and other factors to form chromatin. Chromatin may adopt a tightly condensed conformation that impedes access to transcription factors and is associated with gene silencing, or it may adopt an open, transcription-permissive structure. Closed, condensed chromatin corresponds to the heterochromatic regions, which are very poor in active genes, described by cytologists and cytogeneticists. Open, decondensed chromatin instead characterizes the transcriptionally active euchromatin. Chromatin condensation is linked by posttranslational modification of histones, including acetylation, methylation, and ubiquitination. Evidence that expanded FXN GAA repeats are associated with heterochromatin first came from studies in transgenic mice. When a reporter gene was associated with a long GAA repeat in transgenic mice, it turned out to be silenced in a proportion of cells, resembling a phenomenon known to Drosophila geneticists as position effect variegation. Position effect variegation occurs when a gene is placed in the vicinity of a heterochromatic region and is caused by a spreading of heterochromatin to involve the gene itself. On the basis of the transgenic mice data, it was proposed that the GAA repeat acts as a seed for chromatin condensation, resulting in the silencing of any associated gene.42 According to this view, FXN, or at least part of it, would be included into a heterochromatic region and silenced when it contains an expanded GAA repeat. Recent data indeed show that characteristic heterochromatin-associated posttranslational modifications of histones occur in the vicinity of the expanded GAA repeat in the lymphocyte DNA of patients with FRDA. Changes include an increase in histone H3 lysine 9 (H3K9) trimethylation and a decrease in acetylation at H3K14, H4K5, H4K8, and H4K12, all markers of a heterochromatic state.43 In particular, H3K9 trimethylation is known to trigger binding of heterochromatin protein 1, which then recruits other factors that participate in chromatin condensation and gene silencing.