Directing epigenetic maintenance in normal and malignant haematopoietic stem cells

指导正常和恶性造血干细胞的表观遗传维持

• 批准号: 2753453
• 金额: --
• 依托单位: University of York
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2753453
• 关键词: Directing; epigenetic; maintenance; normal; malignant

Background: The process by which stem cell populations are established and maintained and how individual stem cell clones "compete" is a key component to understanding ageing and cancer. Seminal discoveries in a number of tissues have greatly informed our understanding of degenerative diseases and cancer biology in particular. More recently in the blood system, the high prevalence of age-related clonal haematopoiesis in otherwise healthy individuals has demonstrated that aberrations in clonal competition can be a key indicator of early disease development. Most of these mutations are in epigenetic modifiers (e.g., TET2, DNMT3a, ASXL1) which have further been shown to directly regulate proliferation in blood stem cells. Recently we showed that a protein called CIZ1 influences the stability of at least three different histone modifications, such that they are depleted when CIZ1 is not able to form large assemblies inside the nucleus of cells. We think that these assemblies normally form a shield around selected genes and their histones, to protect them from the enzymes that remove the modifications. Objectives:Establish the role of CIZ1 in primary HSCsUnderstand whether interference with CIZ1 induced shield integrity can destabilize cells in mouse models of malignancyNovelty and TimelinessOur analysis of Cip1-interacting Zinc finger protein 1 (CIZ1) has revealed an unexpected role in high-fidelity maintenance of epigenetic landscape, which appears to contribute to disease avoidance. Null cells derived from genetically modified mice remain viable yet prone to instability, while null animals are prone to haematological malignancies. Nothing has been investigated in primary HSCs, the initiating cells of haematological malignancies and this project will combine CIZ1 expertise and HSC biology expertise in the host laboratories. Both labs are currently MRC-funded for related projects that will accelerate the impact of this student project.Experimental Approach:The project will involve flow cytometry for isolating and characterising blood cell populations, single cell RNA-sequencing, single cell ATAC-sequencing and functional transplantation assays. These techniques will lead to a comprehensive molecular and cellular understanding of CIZ1-deficient HSCs and its impact on haematopoiesis and disease development.

背景资料：干细胞群体的建立和维持过程以及单个干细胞克隆如何“竞争”是理解衰老和癌症的关键组成部分。在许多组织中的精液发现极大地丰富了我们对退行性疾病，特别是癌症生物学的理解。最近在血液系统中，在其他健康个体中与年龄相关的克隆造血的高患病率已经证明克隆竞争中的畸变可以是早期疾病发展的关键指标。这些突变中的大多数是表观遗传修饰剂（例如，TET2、DNMT3a、ASXL1），其已进一步显示直接调节造血干细胞中的增殖。最近，我们发现一种名为CIZ1的蛋白质影响至少三种不同组蛋白修饰的稳定性，当CIZ1不能在细胞核内形成大的组装体时，它们就会被耗尽。我们认为，这些组装体通常会在选定的基因及其组蛋白周围形成一个屏障，以保护它们免受酶的破坏。目的：确定CIZ1在原代HSC中的作用了解干扰CIZ1诱导的屏障完整性是否会使恶性小鼠模型中的细胞不稳定新颖性和时效性我们对Cip1相互作用的锌指蛋白1（CIZ1）的分析揭示了在表观遗传景观的高保真维持中的意想不到的作用，这似乎有助于避免疾病。来自转基因小鼠的造血干细胞仍然存活，但易于不稳定，而无效动物易于发生血液学恶性肿瘤。尚未对原代HSC（血液恶性肿瘤的起始细胞）进行研究，本项目将在宿主实验室结合联合收割机CIZ 1专业知识和HSC生物学专业知识。两个实验室目前都得到了MRC的资助，用于相关项目，这些项目将加速学生项目的影响。实验方法：该项目将涉及用于分离和表征血细胞群的流式细胞术、单细胞RNA测序、单细胞ATAC测序和功能移植分析。这些技术将导致全面的分子和细胞的理解CIZ1缺陷的造血干细胞及其对造血和疾病发展的影响。