Structural biology of chromosome folding and dysregulation in disease

疾病中染色体折叠和失调的结构生物学

• 批准号: MR/W001667/1
• 负责人: Daniel Panne
• 金额: $ 75.96万
• 依托单位: University of Leicester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 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=MR%2FW001667%2F1
• 关键词: Structural; biology; chromosome; folding; dysregulation

The elucidation of the structure of DNA in 1953 kick-started the revolution in life science research and marked the beginning of modern molecular biology. While we do know the structure of DNA at atomic level resolution, it is still mysterious how DNA is packaged in the cell. Human genomic DNA that, if it were stretched out, would reach over two meters in total. In a cell, all this DNA needs to be compacted into a micron-sized nucleus. One basic unit of coiling DNA is the nucleosome, which has for decades been viewed as the first step in condensation of the DNA. However, it is now clear that the main function of nucleosomes is not to enable large-scale genome packaging. Instead, higher-order genome folding is mediated by Structural maintenance of chromosomes (SMC) proteins, an ancient class of ATPases that is found in all domains of life. SMC proteins are large, ring-shaped proteins that act by DNA loop extrusion. While the details are currently unknown, the consequences are that SMC proteins organise DNA into large, dynamic loops. It is becoming increasingly apparent that this chromosome folding reaction is important for many of the most fundamental aspects of genome biology: control of gene regulation by distant regulatory elements, genome replication and repair as well as chromosome segregation during mitosis and meiosis. There are indications that mutation of cohesin subunits plays an important role in a number of cancers and 'cohesinopathies'.We here propose to address two key aspects of this genome folding reaction catalysed by cohesin, on such SMC protein complex. We aim to understand: 1. The structural mechanism of how cohesin catalyses 3D genome folding, and 2. The mechanism that allows cohesin to be deployed during a number of different genome transactions.To achieve these goals, we need to understand better the structure of cohesin holocomplexes and how they interact with DNA and catalyse folding. We also need to address how cohesin interacts with regulators that allow specific deployment during different genome transactions. The different protein subunits of the cohesin complex are mutated in many 'Cohesinopathies' that range from cancer to developmental disorders. More specifically, cohesin dysregulation during meiosis in oocytes can lead to mis-segregation of chromosomes resulting in cells with the wrong number of chromosomes, a hallmark of Down's syndrome (Trisomy 21) and a leading cause of age-related aneuploidy and infertility. Mutations in the cohesin complex are associated with genetic diseases such as Cornelia de Lange and Roberts syndrome which result in severe development defects. Cohesin mutations also can result in genomic instability due to mis-processing of chromosome loops, dysregulation of chromosome replication, repair or segregation. Mis-processing of loops may be at the origin of extrachromosomal DNA loops that overexpress oncogenes and have been identified with high frequency in half of all solid tumor cancers.We therefore need a much better understanding of the molecular mechanisms of cohesin function, regulation and deployment in different chromatin transactions. This will allow us to better understand how mutations contribute to disease. This in turn will allow us to better understand the molecular mechanisms underlying different diseases and to potentially develop new approaches in treatment against cohesin-related cancer and Cohesinopathies. The long-standing challenge will be to understand how the molecular mechanism of genome folding leads to hierarchical genome organisation, and how such organisation leads to emergent properties of genome function (such as long-range gene regulation) and how dysregulation contributes to disease.

1953年DNA结构的阐明开启了生命科学研究的革命，标志着现代分子生物学的开始。虽然我们知道DNA在原子水平上的结构，但DNA在细胞中的包装方式仍然是个谜。人类基因组DNA，如果将其拉伸，将达到两米以上。在细胞中，所有这些DNA都需要被压缩成一个微米大小的细胞核。螺旋DNA的一个基本单位是核小体，几十年来它一直被认为是DNA浓缩的第一步。然而，现在很清楚，核小体的主要功能不是使大规模基因组包装成为可能。相反，高阶基因组折叠是由染色体结构维持（SMC）蛋白介导的，这是一种古老的ATP酶，存在于生命的所有领域。SMC蛋白是通过DNA环挤出起作用的大的环状蛋白。虽然细节目前尚不清楚，但结果是SMC蛋白质将DNA组织成大型动态循环。越来越明显的是，这种染色体折叠反应对于基因组生物学的许多最基本的方面是重要的：通过远距离调控元件控制基因调控、基因组复制和修复以及有丝分裂和减数分裂期间的染色体分离。有迹象表明，cohesin亚基的突变起着重要的作用，在一些癌症和cohesinopathies.We在这里建议解决两个关键方面的cohesin催化的基因组折叠反应，这种SMC蛋白复合物。我们的目标是了解：1。cohesin如何催化3D基因组折叠的结构机制，和2。为了实现这些目标，我们需要更好地了解粘着蛋白全复合物的结构，以及它们如何与DNA相互作用并催化折叠。我们还需要解决粘着蛋白如何与监管机构相互作用，以允许在不同的基因组交易期间进行特定部署。在从癌症到发育障碍的许多“粘连蛋白病”中，粘连蛋白复合物的不同蛋白质亚基发生突变。更具体地，卵母细胞减数分裂期间的粘着蛋白失调可导致染色体的错误分离，导致具有错误数目的染色体的细胞，这是唐氏综合征（21三体）的标志，也是年龄相关的非整倍性和不育的主要原因。粘着蛋白复合物的突变与遗传疾病有关，如导致严重发育缺陷的科尔内利亚德兰格和罗伯茨综合征。由于染色体环的错误加工、染色体复制、修复或分离的失调，粘着蛋白突变也可导致基因组不稳定性。环的错误加工可能是过度表达癌基因的染色体外DNA环的起源，并且在所有实体瘤癌症中以高频率被鉴定，因此我们需要更好地理解粘着蛋白在不同染色质处理中的功能、调节和部署的分子机制。这将使我们更好地了解突变如何导致疾病。这反过来将使我们能够更好地了解不同疾病的分子机制，并有可能开发新的方法来治疗与粘附蛋白相关的癌症和粘附蛋白病。长期存在的挑战将是了解基因组折叠的分子机制如何导致分层基因组组织，以及这种组织如何导致基因组功能的新兴特性（如长距离基因调控）以及失调如何导致疾病。

项目成果

Structural insights into p300 regulation and acetylation-dependent genome organisation.

对P300调节和乙酰化依赖性基因组组织的结构见解。

• DOI: 10.1038/s41467-022-35375-2
• 发表时间: 2022-12-15
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Ibrahim, Ziad;Wang, Tao;Destaing, Olivier;Salvi, Nicola;Hoghoughi, Naghmeh;Chabert, Clovis;Rusu, Alexandra;Gao, Jinjun;Feletto, Leonardo;Reynoird, Nicolas;Schalch, Thomas;Zhao, Yingming;Blackledge, Martin;Khochbin, Saadi;Panne, Daniel
• 通讯作者: Panne, Daniel