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

干细胞和癌症中 USP7-PRC1.6 下游染色质调控机制

• 批准号: MR/X008517/1
• 负责人: Yaser Atlasi
• 金额: $ 55.92万
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX008517%2F1
• 关键词: Mechanisms; chromatin; regulation; downstream; USP7

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.

结直肠癌是西方国家的第四个最常见的癌症与癌症相关的死亡原因，而结直肠肿瘤通常包含各种具有不同形状和成熟水平的肿瘤细胞（与健康组织不同）。癌症的适当功能通常会失去其细胞的身份，但是在我们对健康组织中的分子机制中，这是一个基本的差距对细胞身份的控制并不总是由我们的细胞中的DNA改变。正常的组织和OS在Lader Lader Lader Lader领导者领导者中固定了不受控制的基因Express。 USP7-PRC1.6的观察结果使我们假设USP7-PRC1.6-H2119UB在控制细胞身份方面起着重要的作用。在癌细胞中，在肠道中打开和关闭基因，尤其是在继续再生肠道的肠道细胞中，我们会发现这一过程。通常，当去除USP7-prc1.6时，CER细胞对化学疗法更敏感扭转肠癌。