Switching mammalian genes on and off during development, lineage specification, and differentiation, and its impact on human genetic disease

在发育、谱系规范和分化过程中打开和关闭哺乳动物基因及其对人类遗传疾病的影响

• 批准号: MR/T014067/1
• 负责人: Douglas Higgs
• 金额: $ 300.65万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT014067%2F1
• 关键词: Switching; mammalian; genes; off; during

In animals, life starts with the fertilisation of an egg by a sperm to produce a single cell that will divide and change to produce a fully formed organism. An adult human being is made up of 30 trillion cells that have specialised roles, for example, in the brain, liver, kidney, and blood. All these cells originate from that first single cell. The instructions that tell each cell what to do are contained in DNA. Our DNA is inherited from our parents, and contains 3 billion 'letters' (called bases) organised in 20,000 'words' (called genes). The complete order of letters within the code was established by the Human Genome Project in 2003. Each of our 30 trillion cells contains a copy of the same code and the same 20,000 genes. So how do tissues differ, and perform different roles? Cells behave differently in different tissues in our body because different combinations of genes are switched on and off in different cell types. It is this variation that determines which type of cell (e.g. brain or blood) is made. Imagine that each of your cells was an iPhone: in each case the hardware is identical but, depending on which programmes you switch on, what appears on your screen is quite different. Therefore, one of the major aims in biology at the moment is to understand how a cell decides to switch a particular gene on or off. To do this we must decipher the DNA code, rather like the scientists at Bletchley Park cracked the German 'Enigma' code during the second world war. Our laboratory is trying to crack this code using one particular gene as a model. We know that this gene has the instructions to make haemoglobin, the pigment inside red blood cells. We want to understand how this gene is switched on or off in the bone marrow stem cells. These stem cells can become both red and white blood cells. When a cell makes haemoglobin (turning the gene on) it has decided to become a red blood cell. When it doesn't make haemoglobin (turning the gene off) it has decided to become a white blood cell. Understanding how this process works for one gene will help us understand how it works for many of the other 20,000 genes. Over the last few years we and others have identified three fundamental signals in the code, each comprising 50-300 letters. The first signal is called the gene promoter and it marks the location of the gene and where it starts. This is rather like tuning in to your favourite radio station. The second class of signal is called an enhancer, which acts by modifying the tone and volume of the station into which you have tuned. The third type of signals are called boundary elements and they help the enhancer focus on the chosen station and prevent them drifting off to another station. All three elements work together to make sure that a gene is switched on or off at the right time in development. We are trying to understand how these enhancers, promoters and boundary elements, work together to regulate the production of haemoglobin. We also want to understand how errors in the DNA code can sometimes mean that this control doesn't work properly, leading to human genetic diseases related to anaemia. Our ultimate aim is to use a newly developed technology called genome editing to correct these mistakes in the DNA code.Although our work concentrates on a single gene and the diseases associated with it, understanding the principles behind gene regulation will help us understand how many of the 20,000 genes in our cells are normally switched on and off to form a full human body, and how this goes wrong in inherited diseases such as haemophilia or acquired genetic diseases such as cancer.

在动物中，生命始于卵子与精子的受精，产生一个单细胞，这个单细胞将分裂并变化，产生一个完整的有机体。一个成年人是由30万亿个细胞组成的，这些细胞在大脑、肝脏、肾脏和血液中都有特殊的作用。所有这些细胞都起源于第一个细胞。告诉每个细胞该做什么的指令都包含在DNA中。我们的DNA遗传自父母，包含30亿个“字母”（称为碱基），由2万个“单词”（称为基因）组成。人类基因组计划于2003年确定了密码中完整的字母顺序。我们的30万亿个细胞中的每一个都包含了相同密码的副本和相同的2万个基因。那么组织是如何不同的，扮演着不同的角色呢？细胞在我们身体的不同组织中表现不同，因为不同的基因组合在不同的细胞类型中开启和关闭。正是这种变异决定了形成哪种类型的细胞（如大脑或血液）。想象一下，你的每个细胞都是一部iPhone：在每种情况下，硬件都是相同的，但根据你打开的程序，屏幕上显示的内容却大不相同。因此，目前生物学的主要目标之一是了解细胞如何决定打开或关闭特定基因。要做到这一点，我们必须破译DNA密码，就像二战期间布莱切利公园的科学家破译德国“谜机”密码一样。我们的实验室正试图用一个特定的基因作为模型来破解这个密码。我们知道这种基因有制造血红蛋白的指令，血红蛋白是红细胞内的色素。我们想了解这个基因是如何在骨髓干细胞中开启或关闭的。这些干细胞可以变成红细胞和白细胞。当一个细胞产生血红蛋白（开启基因）时，它就决定变成一个红细胞。当它不产生血红蛋白（关闭基因）时，它就决定变成一个白细胞。了解这个过程是如何对一个基因起作用的，将有助于我们了解它是如何对其他2万个基因起作用的。在过去的几年里，我们和其他人已经确定了密码中的三个基本信号，每个信号由50-300个字母组成。第一个信号被称为基因启动子，它标志着基因的位置和开始的位置。这就像收听你最喜欢的电台一样。第二类信号被称为增强信号，它通过改变你所调谐的电台的音调和音量来起作用。第三种类型的信号被称为边界元素，它们帮助增强器聚焦于选定的站点，防止它们漂移到另一个站点。这三个因素共同作用，以确保基因在发育的正确时间开启或关闭。我们正试图了解这些增强子、启动子和边界元素是如何共同调节血红蛋白的产生的。我们还想了解DNA编码中的错误有时如何意味着这种控制不能正常工作，从而导致与贫血相关的人类遗传疾病。我们的最终目标是使用一种被称为基因组编辑的新技术来纠正DNA密码中的这些错误。虽然我们的工作集中在单个基因和与之相关的疾病上，但了解基因调控背后的原理将有助于我们了解我们细胞中20,000个基因中有多少正常开启和关闭以形成完整的人体，以及在血友病等遗传性疾病或获得性遗传疾病（如癌症）中这是如何出错的。

项目成果

A blood atlas of COVID-19 defines hallmarks of disease severity and specificity.

• DOI: 10.1016/j.cell.2022.01.012
• 发表时间: 2022-03-03
• 期刊: Cell
• 影响因子: 64.5
• 作者: COvid-19 Multi-omics Blood ATlas (COMBAT) Consortium. Electronic address: [e-mail];COvid-19 Multi-omics Blood ATlas (COMBAT) Consortium
• 通讯作者: COvid-19 Multi-omics Blood ATlas (COMBAT) Consortium

Development of LT-HSC-Reconstituted Non-Irradiated NBSGW Mice for the Study of Human Hematopoiesis In Vivo.

• DOI: 10.3389/fimmu.2021.642198
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Adigbli G;Hua P;Uchiyama M;Roberts I;Hester J;Watt SM;Issa F
• 通讯作者: Issa F

Fra-1 regulates its target genes via binding to remote enhancers without exerting major control on chromatin architecture in triple negative breast cancers.

• DOI: 10.1093/nar/gkab053
• 发表时间: 2021-03-18
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Bejjani F;Tolza C;Boulanger M;Downes D;Romero R;Maqbool MA;Zine El Aabidine A;Andrau JC;Lebre S;Brehelin L;Parrinello H;Rohmer M;Kaoma T;Vallar L;Hughes JR;Zibara K;Lecellier CH;Piechaczyk M;Jariel-Encontre I
• 通讯作者: Jariel-Encontre I