Background: The Repeat Expansion Diseases are caused by the intergenerational expansion of a specific tandem repeat. GAA.TTC-repeat expansion in the first intron of the frataxin gene results in a transcription defect that leads to a deficit of frataxin, a protein involved in mitochondrial iron homeostasis. This results in Friedreich ataxia (FRDA), a relentlessly progressive neurodegenerative disease. In addition to the consequences of cerebellar degeneration, FRDA symptoms include diabetes and a frequently fatal hypertrophic cardiomyopathy. Thus the frataxin deficit has consequences outside of the CNS as well. How an intronic repeat affects gene expression is unknown. Previous work from our group and others showed that during transcription in vitro the repeat was able to form a triple-stranded DNA structure (triplex) that trapped the RNA polymerase on the template and reduced the overall yield of transcript (Grabczyk and Usdin, 2000 a,b). However, whether such a triplex forms in the endogenous frataxin locus in vivo is unknown. We have also shown that the normal FXN allele is aberrantly methylated in the region upstream of the repeat and this aberrant methylation is elevated in FRDA patient cells (Greene et. al., 2007). This increased methylation is associated with an elevated level of marks of repressive chromatin in this region. Progress report: We have since gone on to show that repressive chromatin marks extend into the promoter of the FXN gene where they affect both transcription initiation as evidenced by reduced levels of the initiating form of RNA polymerase II and of histone H3 trimethylated on lysine 4 (Kumari, Biacsi and Usdin, 2011). Elongation is also reduced, as evidenced by lower levels of histone H3 trimethylated on lysine 36. These data lend support to the hypothesis that FRDA is in fact an epigenetic disorder. Furthermore, it suggests that agents that reverse these repressive chromatin marks that are currently in phase I clinical trials for the treatment of FRDA, may in fact correct the primary FRDA defect.

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Kumari, Daman; Usdin, Karen (2012) Is Friedreich ataxia an epigenetic disorder? Clin Epigenetics 4:2
Kumari, Daman; Lokanga, Rachel; Yudkin, Dmitry et al. (2012) Chromatin changes in the development and pathology of the Fragile X-associated disorders and Friedreich ataxia. Biochim Biophys Acta 1819:802-10
Kumari, Daman; Biacsi, Rea Erika; Usdin, Karen (2011) Repeat expansion affects both transcription initiation and elongation in friedreich ataxia cells. J Biol Chem 286:4209-15