标题： 计算与分子分析一个X-box顺式调控模块 显示英文标题

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

摘要： 纤毛病是一类以细胞器纤毛功能障碍为特征的人类疾病。 虽然构成纤毛的许多分子成分已经被识别和研究，但关于编码这些成分的基因的转录调控了解较少。 保守的转录因子调节因子X（RFX）/DAF-19通过结合称为X-box的顺式调控基序发挥作用，在从线虫到人类的许多动物中已被证明可以调控纤毛基因。 然而，越来越多的证据表明RFX无法单独启动转录。 因此，可能需要其他因子和顺式调控元件。 其中一个这样的元件是一种称为C-box的DNA基序，最近在C. elegans中被鉴定出来。 目前尚不清楚X-box和C-box是否是唯一涉及的调控元件以及它们如何相互作用。 为此，我分析了dyf-5的转录调控，这是人类纤毛病基因Male-Associated Kinase（MAK）的线虫同源基因。 使用计算方法，我确认了之前报道的X-box和C-box的存在，并鉴定了另一个C-box。 通过依次突变每个鉴定的基序，我确定了每个潜在基序在dyf-5转录调控中的作用。 我的结果表明，只有X-box和三个C-box是必要且足以驱动转录的，其中X-box和中心C-box是主要贡献者，而另外两个C-box则增强表达。 这项研究推进了对一般基因调控的认识，并将加深我们对纤毛病及其导致突变的理解。 显示英文摘要

摘要： 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.