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

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.