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

在动物中，生命始于精子与卵子受精，产生一个单细胞，该细胞将分裂和变化，产生一个完整的有机体。一个成年人由30万亿个细胞组成，这些细胞在大脑、肝脏、肾脏和血液中发挥着特殊的作用。所有这些细胞都起源于第一个单细胞。告诉每个细胞做什么的指令包含在DNA中。我们的DNA从父母那里遗传而来，包含30亿个“字母”（称为碱基），组织成20，000个“单词”（称为基因）。2003年，人类基因组计划确定了密码中字母的完整顺序。我们的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，组织是如何不同的，并发挥不同的作用呢？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被打开和关闭。正是这种变异决定了哪种类型的细胞（例如大脑或血液）。想象一下，你的每一个手机都是一部iPhone：在每一种情况下，硬件都是相同的，但是，根据你打开的程序，屏幕上显示的内容是完全不同的。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，就像布莱切利公园的科学家在第二次世界大战期间破解德国“谜”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。我们知道这个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打开或关闭的。这些干细胞可以变成红细胞和白色血细胞。当一个细胞制造血红蛋白（开启基因）时，它就决定成为一个红细胞。当它不制造血红蛋白（关闭基因）时，它就决定变成一个白色血细胞。了解一个基因的这个过程将有助于我们了解其他20，000个基因中的许多基因是如何工作的。在过去的几年里，我们和其他人已经确定了代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起始位置。这就像是收听你最喜欢的电台。第二类信号被称为增强器，它通过改变你所调谐的电台的音调和音量来起作用。第三类信号称为边界元素，它们帮助增强器聚焦于选定的台站，并防止它们漂移到另一个台站。这三个因素共同作用，以确保基因在发育的正确时间打开或关闭。我们正试图了解这些增强子、启动子和边界元素如何共同作用来调节血红蛋白的产生。我们还想了解DNA密码中的错误有时是如何意味着这种控制不能正常工作的，从而导致与贫血有关的人类遗传疾病。我们的最终目标是使用一种新开发的技术，称为基因组编辑，以纠正这些错误的DNA代码。虽然我们的工作集中在一个单一的基因和与之相关的疾病，了解基因调控背后的原则将有助于我们了解有多少在我们的细胞中的20,000个基因是正常打开和关闭，以形成一个完整的人体，以及在血友病等遗传性疾病或癌症等后天遗传性疾病中，这是如何出错的。

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.