The Epigenetic Modification of CTCF Insulators in Cancer

Abstract

The DNA-binding protein CTCF is a crucial regulatory protein that maintains chromatin boundaries between topologically associated domains (TADs) and is important in regulating proper enhancer/promoter interactions and three-dimensional chromatin architecture. A defining characteristic of CTCF is the profound sensitivity of its binding to DNA methylation. Historically, only mutations of CTCF insulator binding sites have been implicated in cancer development. A recent report has demonstrated that epigenetic changes in methylation at a CTCF insulator is also implicated in the over-expression of an oncogene, leading to cancer. However, this has only been demonstrated in one type of brain cancer. Therefore, this thesis takes a computational approach to examine the effects of epigenetic changes at CTCF insulators in lung cancer. The analysis shows that the majority of CTCF insulators do not appear to be differentially methylated in the A549 lung carcinoma cell line. Furthermore, differential DNA methylation at CTCF insulators in the A549 lung carcinoma cell line was not correlated with a genome wide change in gene expression. However, an analysis of 10 highly differentially methylated insulators in A549 cells found inappropriate expression of several neighboring potential oncogenes, such as NEDD8 and PRMT1, and tumor suppressors, GLTSCR2 and IL32, as a result of potential insulator dysfunction. These results suggest that DNA methylation of CTCF insulators is important in the development of lung cancer and can result in the increase or decrease in expression of oncogenes and tumor suppressor respectively. Further studies should experimentally investigate the significance of the identified oncogene and tumor suppressor candidates in lung cancer development.