Colorectal cancer cells lose chemical tags called methyl groups from large stretches of “junk” DNA where no active genes sit, and this project aims to find out why that happens and what it does to the tumour. DNA methylation normally silences repetitive, gene-free regions of the genome—known as heterochromatin—to keep the cell stable. In colorectal cancer, which causes roughly 10% of UK cancer deaths, that methylation vanishes. The researchers have identified a gene, DNMT3B, that places methyl tags on heterochromatin, and they suspect its failure is a key early event in cancer development. They will study colorectal cancer cells in the lab to work out exactly what goes wrong when heterochromatin loses its methylation, how DNMT3B normally deposits those tags, and how the loss changes as cancer progresses. This is fundamental science: it will not produce a new treatment tomorrow. But understanding the mechanism could reveal whether targeting DNMT3B is a viable therapeutic strategy for colorectal cancer. Because similar methylation loss occurs in many other cancers, the findings may apply broadly. The work may also shed light on a rare genetic syndrome—Immunodeficiency Centromeric Instability and Facial Anomalies Syndrome Type 1—caused by DNMT3B mutations, where heterochromatin is already undermethylated.
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All our cells contain the same DNA and the same genes. However, not all genes are needed in every cell type. Cells can turn off genes that are not needed in several ways. One of these is by chemically modifying DNA by methylating it. When people develop cancer, the patterns of DNA methylation change. Scientists believe these changes could play a crucial role in the helping tumours grow. There's a lot of interest in finding ways to manipulate these DNA methylation changes as a cancer treatment or to use them to help diagnose cancer. However, we are not sure how why these DNA methylation changes happen in cancer. This makes it hard to understand how important they are and to use them to help treat patients. One of the most common changes in DNA methylation in cancer is its loss from parts of the genome where genes are absent or inactive which scientists call heterochromatin. We have found that a gene known as DNMT3B is important in placing DNA methylation on the heterochromatic part of the genome. We think this observation could be a key that helps unlock our understanding of why cancers might lose methylation from heterochromatin and how that promotes cancer. In this project, we will investigate this further in the laboratory by studying colorectal cancer, a type of cancer where DNMT3B seems to play an important role in causing the disease. Specifically, we want to know: • What goes wrong in cells when the heterochromatic part of the genome losses DNA methylation. • How DNA methylation gets placed at on the heterochromatic part of the genome. • How the heterochromatic part of the genome changes during the development of cancer. Our study will help us understand how changes in DNA methylation contribute to colorectal cancer, which causes around 10% of cancer deaths in the UK. We will help understand whether it might be possible to treat colorectal cancer by targeting DNMT3B in the future. Since similar losses of DNA methylation are seen in other cancers, our findings could have broader applications for cancer research and treatment. Furthermore, some people are born with a rare genetic syndrome known as Immunodeficiency Centromeric Instability and Facial Anomalies Syndrome Type 1. This is caused by mutations in DNMT3B, and the cells of these people have little DNA methylation in the heterochromatic part of the genome. It is possible our results could help us understand why DNMT3B mutations cause this syndrome.
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