Altered Nucleosome Positioning at the Transcription Start Site and Deficient Transcriptional Initiation in Friedreich Ataxia

作者：Chutake Yogesh K; Costello Whitney N; Lam Christina; Bidichandani Sanjay I^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2014, 289(22): 15194-15202.

DOI：10.1074/jbc.M114.566414

• Gene Transcription
• Heterochromatin
• Neurological Diseases
• Nucleotide Repeat Disease
• Transcription Promoter
• Friedreich Ataxia
• Expanded Triplet Repeat
• Nucleosome Positioning
• Transcription Start Site

Background: Friedreich ataxia (FRDA) is caused by an expanded GAA triplet repeat (GAA-TR) mutation that results in FXN transcriptional deficiency. Results: Repressive chromatin spreads from the expanded GAA-TR mutation, switching off the FXN gene promoter. Conclusion: Reduced transcriptional initiation is the major cause of FXN transcriptional deficiency in FRDA. Significance: Reactivation of FXN transcriptional initiation is a potential therapeutic strategy in FRDA.
Most individuals with Friedreich ataxia (FRDA) are homozygous for an expanded GAA triplet repeat (GAA-TR) mutation in intron 1 of the FXN gene, which results in deficiency of FXN transcript. Consistent with the expanded GAA-TR sequence as a cause of variegated gene silencing, evidence for heterochromatin has been detected in intron 1 in the immediate vicinity of the expanded GAA-TR mutation in FRDA. Transcriptional deficiency in FRDA is thought to result from deficient elongation through the expanded GAA-TR sequence because of repeat-proximal heterochromatin and abnormal DNA structures adopted by the expanded repeat. There is also evidence for deficient transcriptional initiation in FRDA, but its relationship to the expanded GAA-TR mutation remains unclear. We show that repressive chromatin extends from the expanded GAA-TR in intron 1 to the upstream regions of the FXN gene, involving the FXN transcriptional start site. Using a chromatin accessibility assay and a high-resolution nucleosome occupancy assay, we found that the major FXN transcriptional start site, which is normally in a nucleosome-depleted region, is rendered inaccessible by altered nucleosome positioning in FRDA. Consistent with the altered epigenetic landscape the FXN gene promoter, a typical CpG island promoter, was found to be in a transcriptionally non-permissive state in FRDA. Both metabolic labeling of nascent transcripts and an unbiased whole transcriptome analysis revealed a severe deficiency of transcriptional initiation in FRDA. Deficient transcriptional initiation, and not elongation, is the major cause of FXN transcriptional deficiency in FRDA, and it is related to the spread of repressive chromatin from the expanded GAA-TR mutation.

• 出版日期2014-5-30