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

结直肠癌是西方国家癌症相关死亡的第四大常见原因和第二大原因，每年给NHS带来超过17亿英镑的负担。结直肠肿瘤通常包含多种不同形状和成熟程度（分化）的肿瘤细胞。在健康组织中，细胞特性受到严格调节，以确保器官的正常功能，而在肿瘤中，癌细胞往往失去细胞特性，变得更加恶性。然而，对于控制健康组织（如肠）和癌症组织（如结直肠肿瘤）中细胞身份的分子机制，我们的知识存在根本性的差距。很明显，细胞身份的控制并不总是由DNA的改变引起的。在我们的细胞中，DNA与蛋白质结合形成一种叫做染色质的结构。染色质蛋白可以添加特定的化学修饰，决定基因何时以及如何开启和关闭。这一染色质调控过程对于控制正常组织中的细胞身份是重要的，并且在癌症中经常被解除调控，导致基因表达失控。我们最近发现，一种名为USP7-PRC1.6的特定蛋白质复合物增加了染色质上名为H2AK119Ub的特定化学修饰的水平。我们还发现这种分子机制对于关闭基因表达很重要。此外，我们注意到，在健康肠道和结直肠肿瘤中，具有高水平USP7-PRC1.6的细胞成熟（分化）程度较低。这些观察结果使我们假设USP7-PRC1.6-H2Ak119Ub在控制细胞身份中起重要作用。本课题旨在探讨USP7-PRC1.6在健康肠道和结直肠癌中调控细胞特性的分子机制。首先，我们将研究USP7-PRC1.6如何控制染色质的H2AK119Ub化学修饰。探索这一过程对于理解癌细胞中基因是如何开启和关闭的非常重要。其次，USP7-PRC1.6蛋白在健康肠道中的功能，特别是在不断再生肠内膜的肠道干细胞中的功能尚不清楚。我们将发现当USp7-PRC1.6被移除后，肠道干细胞是否能够正常运作。最后，我们将确定当我们阻断USP7-PRC1.6的功能时，结直肠癌细胞是否对化疗药物更敏感。了解这些分子机制与我们对健康和疾病的理解有着巨大的相关性，并将帮助我们改进结直肠癌的治疗策略。

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.