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.

在西方国家，结直肠癌是与癌症相关的死亡的第四位最常见的原因，也是第二大原因，NHS每年的负担超过17亿GB。结直肠肿瘤通常含有各种不同形状和成熟程度(分化)的肿瘤细胞。与健康组织不同，在健康组织中，细胞身份受到严格监管，以确保器官的正常功能，而在肿瘤中，癌细胞往往失去细胞身份，变得更加恶性。然而，我们对控制健康组织(例如肠道)和癌症(例如结直肠癌)细胞特性的分子机制的了解存在着根本的差距。细胞特性的控制并不总是由DNA的改变引起，这一点已经变得很明显。在我们的细胞中，DNA与蛋白质结合形成一种称为染色质的结构。染色质蛋白质可以添加特定的化学修饰，这决定了基因何时以及如何打开和关闭。这一染色质调节过程对控制正常组织中的细胞特性很重要，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的特定蛋白质复合体增加了染色质上一种名为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是重要的。此外，我们还注意到，在健康肠道和结直肠肿瘤中，USP7-PRC1.6水平高的细胞成熟(分化)较少。这些观察结果使我们假设USP7-PRC1.6-H2Ak119Ub在控制细胞识别方面发挥着重要作用。本研究旨在探讨USP7-PRC1.6在健康肠道和结直肠癌中控制细胞特性的分子机制。首先，我们将研究USP7-PRC1.6是如何控制染色质的H2AK119 Ub化学修饰的。探索这一过程对于了解癌细胞中基因是如何开启和关闭的很重要。其次，USP7-PRC1.6蛋白在健康肠道中的功能，特别是在持续再生肠壁的肠道干细胞中的功能，尚不清楚。当USP7-PRC1.6被移除时，我们将发现肠道干细胞是否能够正常功能。最后，我们将确定阻断USP7-PRC1.6的S功能是否会使结直肠癌细胞对化疗药物变得更加敏感。了解这些分子机制与我们对健康和疾病的理解具有巨大的相关性，并将有助于我们改进结直肠癌的治疗策略。