RTD Success Stories - Unlocking the secrets of cell behaviour
Non-genetic material is material that is not part of the chromosomes, the chains in the cell nucleus which contain the genes. Genes are the sequence of nucleic acids which provide the assembly instructions for a living organism, and determine how it will function. The Epicentromere project, which was completed in March 2012, focused on the inner workings of the cell and addressed the underlying question of inheritance – what exactly is inherited, and how. A major breakthrough was that it successfully enhanced our understanding of how genes are turned off. The implication of this discovery at the molecular level could be huge, helping scientists to better understand how gene expression is controlled. Indeed, the ultimate goal, explains project coordinator Dr Lars Jansen, was to get a better handle on controlling the expression of genes going astray, as in tumours. "It is now clear that for tumour formation, you don’t necessarily need a mutant gene," he concludes. "There could be a defect in the switches sitting on top of the gene." In other words, there could be a defect in the machinery that controls genes. The next generation For years, scientists thought that only genes were passed from parents to offspring, and that DNA (Deoxyribonucleic acid, which encodes the genetic instruction given during the development and the functioning of a living organism), was the only carrier of genetic information. Everything else was merely a product of these genes. "That view has been modified for a while, as there was a growing acceptance that there must be something else," explains Dr Jansen. "Cells that divide have different functions and shapes – muscle cells, neuron cells and so on. When they divide they pass on their DNA, but they must also pass on something else, because all cells have the same genes. There has to be something in addition that tells the cell – I am a muscle cell." What we know now is that while cells carry all genes, not all genes are necessarily switched on. A muscle gene, for example, will have a liver-specific gene switched off. "But there must be molecules that control this cellular identity, that control, if you like, the switches," says Dr Jansen. "What is new is that whatever gene is turned off will stay turned off; this is inherited." Finding out how this information is maintained has been the goal of the project. However, instead of looking at genes, the project focused on the 'centromere', the part of the chromosome (a long structure of DNA found in the cell nucleus, containing all the characteristics of a living organism) that controls its behaviour. The Epicentromere team found that the position of the centromere was always specified by certain proteins, not directly by arrangement of the DNA, as is the case for genes. They wanted to know what it was that made this group of proteins inheritable. Using fluorescent microscopes, the team sought to uncover exactly what was happening to these proteins at the time of cell division. Dr Jansen found that when cells divide, not only do the genes split in two but also the centromere proteins were divided up between the daughter cells. But this begged the question: if for example you start with ten proteins, and then split into five, how long can this go on before the proteins are diluted out? Dr Jansen surmised that there had to be a mechanism not only to divide the proteins, but also to produce them and put them in the right place. An important inheritance This is epigenetic inheritance – i.e. inheritance above the level of genes. This means that heritable changes in gene expression are caused by mechanisms other than changes in the underlying DNA sequence. Epicentromere's success in this field came from uncovering the mechanism by which cells recruit new proteins. This must happen only once during the cell cycle, or there will be either too many or too few proteins and the mechanism they control will go astray. "We discovered that this mechanism happens after the cell is divided, and how this is controlled," says Dr Jansen. "We found an adaptor, or bridging molecule, which fits to an old protein and a new one. In this way, the cell ensures the old protein is replaced at the right place and the right moment." The Epicentromere project proved that something other than DNA can be inherited and, importantly, how this inheritance is controlled in space and time. This represents a major step in understanding the role of epigenetic systems. - Project full name: Determining the epigenetic mechanism of centromere propagation - Project acronym: Epicentromere - Project reference number: 224874 - Name/country of project coordinator: Fundacao Calouste Gulbenkian, Portugal - Total project cost: EUR 100 000 - EC contribution: EUR 100 000 - Project start/end: April 2008 to March 2012