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，生命始于精子对鸡蛋的施肥，以产生一个单个细胞，该细胞会分裂并改变以产生完全形成的生物体。一个成年人由30万亿个细胞组成，这些细胞在大脑，肝脏，肾脏和血液中，例如在大脑，肝脏，肾脏和血液中。所有这些细胞源自第一个单元。 DNA中包含说明每个细胞的说明。我们的DNA是从父母那里继承的，其中包含30亿个“字母”（称为碱），用20,000“单词”（称为基因）组织。代码中的完全字母顺序是由2003年人类基因组项目确定的。我们30万亿个单元中的每个单元都包含相同代码和相同20,000个基因的副本。那么组织如何不同并发挥不同的作用？细胞在我们体内的不同组织中的行为不同，因为不同细胞类型的不同基因组合被打开和关闭。正是这种变异决定了制造哪种类型的细胞（例如脑或血液）。想象一下，您的每个单元格是iPhone：在每种情况下，硬件都是相同的，但是根据您打开的程序，屏幕上出现的内容大不相同。因此，目前生物学的主要目的之一是了解细胞决定如何打开或关闭特定基因。为此，我们必须破译DNA代码，就像Bletchley Park的科学家在第二次世界大战期间破解了德国的“谜”守则。我们的实验室正在尝试使用一个特定基因作为模型来破解此代码。我们知道该基因具有使血红蛋白（红细胞内的色素）的指示。我们想了解该基因如何在骨髓干细胞中打开或关闭。这些干细胞可以成为红色和白细胞。当细胞产生血红蛋白（打开基因）时，它已决定成为红细胞。当它不会使血红蛋白（关闭基因关闭）时，它已决定成为白细胞。了解一个基因的过程如何工作，将有助于我们了解其对其他20,000个基因的工作原理。在过去的几年中，我们和其他人在代码中确定了三个基本信号，每个信号包括50-300个字母。第一个信号称为基因启动子，它标志着基因的位置及其开始的位置。这很像在您最喜欢的广播电台中调音。第二类信号称为增强器，该增强剂通过修改您调整的站点的音调和音量来起作用。第三类信号称为边界元素，它们有助于增强器专注于所选站点，并防止它们漂流到另一个站点。这三个元素共同起作用，以确保在合适的开发时间打开或关闭基因。我们正在尝试了解这些增强剂，启动子和边界要素如何共同调节血红蛋白的产生。我们还想了解DNA代码中的错误有时意味着该控制无法正常工作，从而导致与贫血有关的人类遗传疾病。我们的最终目的是使用一种称为基因组编辑的新技术来纠正DNA代码中的这些错误。尽管我们的工作集中于单个基因和与之相关的疾病，了解基因法规背后的原理将有助于我们在细胞中的20,000个基因中有多少个基因在我们的细胞中有多少正常的人类和遗传性疾病中的遗传性疾病，例如，这种疾病的疾病正常出现在遗传上，例如，遗传性疾病是出于遗传性的。

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.