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Title: Heterochromatin effects in Friedreich's ataxia and sexual dimorphism
Author: Yandim, Cihangir
ISNI:       0000 0004 2724 0442
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Heterochromatin is implicated in the negative regulation of gene expression. To understand the effects of heterochromatin on RNA polymerase-II (RNAPII) mediated transcription, this study focused on the FXN gene where abnormal silencing induced by expanded (GAA)n repeats causes Friedreich's ataxia (FRDA), an incurable neurological disorder. Here, the silenced FXN locus was found to be modified by the heterochromatic histone marks H3K9me3, H3K27me3 and bound by HP1β. This pathological heterochromatinisation was partially reversed by the histone deacetlyase inhibitor nicotinamide, which upregulated FXN expression to potentially therapeutic levels in vitro, ex vivo and in vivo. In addition, RNAPII was shown to be stalled in the first exon of the FXN gene and degraded by the proteasome in FRDA but not in healthy cells. This was linked to increased proteasome binding at the -silenced FXN locus in a pattern reminiscent of the heterochromatin marks. Importantly, proteasome inhibition restored stalled RNAPII levels in FRDA and upregulated FXN to potentially therapeutic levels in vitro. Moreover, experiments with healthy human cells and wild-type mouse thymus revealed enriched levels of proteasome binding in other heterochromatic regions (e.g. pericentromeric repeats and SINEs) which were also de-repressed by proteasome inhibition; suggesting that the effect seen on the pathological FXN locus represented a specific example of a more generalised phenomenon. Overall, this introduces a novel mechanism whereby heterochromatin might be maintained in a silent state. In this thesis, heterochromatin effects were also investigated in relation to sexually dimorphic gene expression. Microarray analyses revealed hundreds of autosomal genes sensitive to sex chromosome-complement rather than gender. HP1β-repressed genes and SINE elements were over-represented within this gene group suggesting a potential link between heterochromatin, proteasome-dependent silencing and sexually dimorphic gene expression. The results reveal a novel layer in the regulation of sexually dimorphic genes with implications for understanding sex-bias in physiology and disease.
Supervisor: Festenstein, Richard Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral