Mechanisms of chromatin regulation downstream of USP7-PRC1.6 in stem cells and cancer

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Colorectal cancer is the 4th most common and the 2nd leading cause of cancer related deaths in western countries, with a burden of over £1.7 billion per year on the NHS. Colorectal tumours often contain a variety of tumour cells that have different shapes and maturation levels (differentiation). Unlike healthy tissues in which cell identity is tightly regulated to ensure the proper function of the organ, in tumours, cancer cells often lose their cell identity and become more malignant. However, there is a fundamental gap in our knowledge about the molecular mechanisms that control cell identity in healthy tissues (for example intestine) and in cancers (for example colorectal tumours). It has become apparent that control of cell identity is not always caused by alterations in the DNA. In our cells, DNA is associated with proteins to form a structure called chromatin. Chromatin proteins can add specific chemical modifications which determine when and how genes are turned on and off. This process of chromatin regulation is important for controlling cell identity in normal tissues and is often deregulated in cancer leading to uncontrolled gene expression. We recently discovered that a specific protein complex called USP7-PRC1.6 increases the level of a specific chemical modification called H2AK119Ub at chromatin. We also found that this molecular mechanism is important for turning off gene expression. In addition, we have noticed that cells that have high level of USP7-PRC1.6, are less maturated (differentiated) in healthy intestine and in colorectal tumours. These observations lead us to hypothesize that USP7-PRC1.6-H2Ak119Ub plays an important role in controlling cell identity. This research proposal aims to explore the molecular mechanisms by which USP7-PRC1.6 controls cellular identity in healthy intestine and in colorectal cancer. First, we will investigate how the USP7-PRC1.6 controls the H2AK119Ub chemical modification of chromatin. Exploring this process is important to understand how genes are turned on and off in cancer cells. Secondly, the function of USP7-PRC1.6 proteins in healthy intestine and in particular in intestinal stem cells that continuedly regenerate the intestinal lining, is not known. We will find out whether intestinal stem cells are able to function normally when the USp7-PRC1.6 is removed. Lastly, we will determine whether colorectal cancer cells become more sensitive to chemotherapy drugs when we block USP7-PRC1.6's function. Understanding these molecular mechanisms is of huge relevance to our understanding of health and disease and will help us to improve treatment strategies in colorectal cancer.