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

肿瘤细胞在体内所有组织中的一个共同特征是DNA甲基化的基因组景观发生了巨大变化-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，而具有显著更密集甲基化的区域（称为CpG岛）最常见于启动子区域，并与受抑制的基因表达相关。据预测，这种减少的基因表达是DNA甲基化和转录因子之间相互作用的结果，由此DNA甲基化标记可以直接阻碍转录因子结合或转录因子的募集以编辑局部表观遗传景观。然而，目前几乎没有证据支持这种相互作用的机制模型。在肿瘤细胞中，在整个基因组中观察到显著的低甲基化，同时许多高甲基化的启动子区域也是明显的。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诸如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增殖和细胞周期的进展。因此，我们的目的是询问与正常细胞基因组数据相比，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，由此建立的甲基QTL可以用于确定癌症基因组中与DNA甲基化的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.