Definition of The Landscape of Chromatin Structure At The Frataxin Gene In Friedreich’S Ataxia

<p>Friedreich’s ataxia (FRDA) is caused by the transcriptional silencing of the frataxin (<em>FXN</em>) gene. FRDA patients have expansion of GAA repeats in intron 1 of the <em>FXN</em> gene in both alleles. A number of studies demonstrated that specific histone deacetylase inhibitors (HDACi) affect either histone modifications at the <em>FXN</em> gene or <em>FXN</em> expression in FRDA cells, indicating that the hyperexpanded GAA repeat may facilitate heterochromatin formation. However, the correlation between chromatin structure and transcription at the <em>FXN</em> gene is currently limited due to a lack of more detailed analysis. Therefore, I analyzed the effects of the hyperexpanded GAA repeats on transcription status and chromatin structure using lymphoid cell lines derived from FRDA patients. Using chromatin immunoprecipitation and quantitative PCR, I observed significant changes in the landscape of histone modifications in the vicinity of the GAA tract in FRDA cells relative to control cells. Similar epigenetic changes were observed in GFP reporter construct containing 560 GAA repeats. Further, I detected similar levels of <em>FXN</em></p> <p>pre-mRNA at a region upstream of hyperexpanded GAA repeats in FRDA and control cells, indicating similar efficiency of transcription initiation in FRDA cells. I also showed that histone modifications associated with hyperexpanded GAA repeats are independent of transcription progression using the GFP reporter system. My data strongly support evidence that <em>FXN</em> deficiency in FRDA patients is consequence of defective transition from initiation to elongation of <em>FXN</em> transcription due to heterochromatin-like structures formed in the proximity of the hyperexpanded GAAs.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2011

Author dc:creator

• Kim, Eunah

Contributors dc:contributor

• Sharon Y. R. Dent, Ph.D.
• Michelle C. Barton, Ph.D.
• Pierre McCrea, Ph.D.

• Epigenetics
• Chromatin Structure
• Histone Modification
• Frataxin
• FRDA
• Neurodegenerative Disease
• Repetitive DNA
• Triplet repeat
• Repeat Diseases
• Biochemistry
• Cell Biology
• Molecular and Cellular Neuroscience
• Molecular Biology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/206

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1235