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Computational and molecular dissection of an X-box cis-Regulatory module

Resource type
Thesis type
(Thesis) Ph.D.
Date created
2015-10-06
Authors/Contributors
Abstract
Ciliopathies are a class of human diseases marked by dysfunction of the cellular organelle, cilia. While many of the molecular components that make up cilia have been identified and studied, comparatively little is understood about the transcriptional regulation of genes encoding these components. The conserved transcription factor Regulatory Factor X (RFX)/DAF-19, which acts through binding to the cis-regulatory motif known as X-box, has been shown to regulate ciliary genes in many animals from Caenorhabditis elegans to humans. However, accumulating evidence suggests that RFX is unable to initiate transcription on its own. Therefore, other factors and cis-regulatory elements are likely required. One such element, a DNA motif called the C-box, has recently been identified in C. elegans. It is still unclear if the X-box and C-boxes are the only regulatory elements involved and how they interact. To this end, I analyzed the transcriptional regulation of dyf-5, the C. elegans ortholog of the human ciliopathy gene Male-Associated Kinase (MAK). Using computational methods, I was able to confirm the presence of the previously reported X-box and C-boxes as well as identifying an additional C-box. By sequentially mutating each of the identified motifs, I identified the role each potential motif plays in transcriptional regulation of dyf-5. My results showed that only the X-box and the three C-boxes are necessary and are sufficient to drive transcription, with the X-box and the centre C-box being the major contributors and the other two C-boxes enhancing expression. This study advances the knowledge of gene regulation in general and will further our understanding of ciliopathies and the mutations that cause them.
Document
Identifier
etd9300
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This thesis may be printed or downloaded for non-commercial research and scholarly purposes.
Scholarly level
Supervisor or Senior Supervisor
Thesis advisor (ths): Chen, Jack
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etd9300_TWarrington.pdf 2.24 MB

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