Chromatin changes in the development and pathology of the Fragile X-associated disorders and Friedreich ataxia

Abstract

The Fragile X-associated disorders (FXDs) and Friedeich ataxia (FRDA) are genetic conditions resulting from expansion of a trinucleotide repeat in a region of the affected gene that is transcribed but not translated. In the case of the FXDs, pathology results from expansion of CGG•CCG-repeat tract in the 5′ UTR of the FMR1 gene, while pathology in FRDA results from expansion of a GAA•TTC-repeat in intron 1 of the FXN gene. Expansion occurs during gametogenesis or early embryogenesis by a mechanism that is not well understood. Expansion then produces disease pathology in various ways that are not completely understood either. In the case of the FXDs, alleles with 55–200 repeats express higher than normal levels of a transcript that is thought to be toxic, while alleles with >200 repeats are silenced. In addition, alleles with >200 repeats are associated with a cytogenetic abnormality known as a fragile site, which is apparent as a constriction or gap in the chromatin that is seen when cells are grown in presence of inhibitors of thymidylate synthase. FRDA alleles show a deficit of the FXN transcript. This review will address the role of repeat-mediated chromatin changes in these aspects of FXD and FRDA disease pathology.

DNA Triplet Repeat Expansion and Mismatch Repair

“…Likewise, although expanded (and methylated) CGG·CCG and expanded GAA·TTC repeats exclude nucleosomes in vitro (163–165), these sequences adopt tightly condensed heterochromatin configurations in vivo that mediate the gene-silencing effects underlying the pathogenesis of both FRDA and FRAXA (24, 166, 167). Attenuation of gene expression by expanded GAA·TTC repeats in FRDA cell lines and mouse models is associated with hypoacetylation of histones H3 and H4, and can be reversed by treatment with histone deacetylase (HDAC) inhibitors (168, 169).…”

“…FRAXA and FRDA are the best-characterized examples of loss-of-function diseases, wherein expansion of CGG·CCG and GAA·TTC repeats, respectively, results in epigenetic changes within the corresponding genes, culminating in heterochromatin-mediated transcriptional silencing of these genes (24). Thus, decreased levels of FMRP and frataxin polypeptides, respectively, are hallmarks of FRAXA and FRDA.…”

Precarious maintenance of simple DNA repeats in eukaryotes

“…Disease pathology, in turn, often results from an expanded repeat acquiring dominant gain-of-function at the RNA and/or protein levels [6,7]. In addition, long repeat tracts can also lead to the repression of the genes in which they are located, typically by promoting heterochromatin formation [8]. …”

Activating frataxin expression by repeat-targeted nucleic acids

“…Unlike neurological diseases such as Huntington Disease that are caused by the expression of mutant protein, patients with FRDA express normal FXN protein but do so at a reduced level. The progression of the disease would likely be slowed if FXN levels could be enhanced and agents that increase expression of FXN are a promising approach to therapy 7 8 9 10 .…”