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

基本信息

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

项目摘要

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，生命始于精子使卵子受精，产生单个细胞，该细胞将分裂并变化以产生完全形成的有机体。成年人由 30 万亿个细胞组成，这些细胞具有特殊的作用，例如大脑、肝脏、肾脏和血液。所有这些细胞都源自第一个单细胞。 DNA 中包含告诉每个细胞做什么的指令。我们的 DNA 遗传自父母，包含 30 亿个“字母”（称为碱基），组成 20,000 个“单词”（称为基因）。代码中字母的完整顺序是由人类基因组计划于 2003 年建立的。我们 30 万亿个细胞中的每一个都包含相同代码的副本和相同的 20,000 个基因。那么组织有何不同并发挥不同的作用呢？我们体内不同组织中的细胞表现不同，因为不同的细胞类型中开启和关闭的基因组合不同。正是这种变异决定了细胞类型（例如大脑或血液）的形成。想象一下，你的每个手机都是一部 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截然不同。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。为此，我们必须破译 DNA 密码，就像第二次世界大战期间布莱奇利公园的科学家破解了德国“恩尼格玛”密码一样。我们的实验室正在尝试使用一个特定的基因作为模型来破解这一密码。我们知道该基因具有制造血红蛋白（红细胞内的色素）的指令。我们想了解该基因如何在骨髓干细胞中打开或关闭。这些干细胞可以变成红细胞和白细胞。当细胞产生血红蛋白（打开基因）时，它就决定成为红细胞。当它不能产生血红蛋白（关闭基因）时，它就决定成为白细胞。了解这一过程如何作用于一个基因将有助于我们了解它如何作用于其他 20,000 个基因。在过去的几年里，我们和其他人在代码中识别出了三个基本信号，每个信号由 50-300 个字母组成。第一个信号称为基因启动子，它标记基因的位置及其起始位置。这很像收听您最喜欢的广播电台。第二类信号称为增强器，它通过修改您所调谐的电台的音调和音量来起作用。第三种类型的信号称为边界元素，它们帮助增强器聚焦于所选站点并防止它们漂移到另一个站点。所有三个要素共同作用，确保基因在发育的正确时间打开或关闭。我们试图了解这些增强子、启动子和边界元件如何共同作用来调节血红蛋白的产生。我们还想了解 DNA 代码中的错误有时会导致这种控制无法正常工作，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称为基因组编辑的新开发技术来纠正 DNA 代码中的这些错误。虽然我们的工作集中于单个基因及其相关疾病，但了解基因调控背后的原理将帮助我们了解有多少我们细胞中的 20,000 个基因通常会打开和关闭以形成完整的人体，以及在血友病等遗传性疾病或癌症等获得性遗传疾病中，这种情况是如何出错的。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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: julian.knight@well.ox.ac.uk;COvid-19 Multi-omics Blood ATlas (COMBAT) Consortium
通讯作者：
COvid-19 Multi-omics Blood ATlas (COMBAT) Consortium

Super-enhancers require a combination of classical enhancers and novel facilitator elements to drive high levels of gene expression

DOI：
10.1101/2022.06.20.496856
发表时间：
2022-06-24
期刊：
bioRxiv
影响因子：
0
作者：
Blayney, J. W.;Francis, H.;Kassouf, M.
通讯作者：
Kassouf, M.

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

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