Investigating the relationship between transcription factors and DNA methylation in breast cancer.

在人体所有组织中，肿瘤细胞的一个共同特征是DNA甲基化的基因组格局发生了戏剧性的变化--这是一种表观遗传修饰，已被证明可以调节染色质结构和基因表达。DNA甲基化在正常细胞基因组中普遍存在，而甲基化密度明显较高的区域，称为CpG岛，最常发现于启动子区域，与抑制基因表达有关。据预测，这种基因表达的降低是DNA甲基化和转录因子相互作用的结果，DNA甲基化标记可能直接阻碍转录因子结合或招募转录因子来编辑局部表观遗传格局。然而，目前几乎没有证据支持这种相互作用的机械论模型。在肿瘤细胞中，在整个基因组中观察到明显的低甲基化，同时也明显地存在一些高甲基化的启动子区域。这种表型可能表明DNA甲基化和转录因子之间的相互作用在癌基因激活和肿瘤抑制基因的失调等过程中发挥作用，这些过程负责控制细胞周期的增殖和进展。因此，我们的目的是通过与正常细胞基因组数据的比较来询问癌细胞中DNA甲基化和转录因子之间的关系。这可以使用遗传方法来实现，从而可以使用已建立的方法QTL来确定癌症基因组中与DNA甲基化显著变化相关的基因组区域。

A common feature of tumour cells, across all tissues in the body, is a dramatic change in the genomic landscape of DNA methylation - a epigenetic modification which has been shown to regulate chromatin structure and gene expression. DNA methylation is observed globally in normal cell genomes, whilst regions with significantly more dense methylation, called CpG islands, are most commonly found in promoter regions and associate with repressed gene expression. It is predicted that this reduced gene expression is a consequence of the interactions between DNA methylation and transcription factors, whereby DNA methylation marks may either directly impede transcription factor biding or the recruitment of transcription factors to edit the local epigenetic landscape. However, there is currently little evidence to support a mechanistic model for this interaction. In tumour cells, there is marked hypomethylation observed across the genome, whilst a number of hypermethylated promoter regions are also evident. This phenotype may suggest that the interaction between DNA methylation and transcription factors has a role in processes such as oncogene activation and the dysregulation of tumour suppressor genes, which are responsible for controlling cell proliferation and progression through the cell cycle. Therefore, our aim is to interrogate the relationship between DNA methylation and transcription factors in cancer cells in comparison with normal cell genomic data. This can be achieved using genetic approaches, whereby established methQTLs can be used to determine genomic regions in cancer genomes which associate with significant changes in DNA methylation.