Establishment, Maintenance and Modulation of heterochromatin domains

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The DNA of our genome contains the instructions, or code, to make cells and to make a person. Some of the DNA sequences (genes) in our cells code for making proteins. However, much of our DNA is made up of repeat sequences that do not code for proteins. For example, the human genome contains 46% repeat sequences. Other genomes contain even higher proportions of repeats (e.g. 65% for maize). The function of these repeats is not well understood. However, it is understood that repetitive sequences spell trouble for the cell. This is because repetitive sequences tend to be 'unstable' and can interact and fuse with other repeat sequences in other places in the genome. This means the genome can become rearranged, causing loss of some sequences and duplication of others. It can also bring two separate sections of the genome together which can mess up the instructions for making the right amounts of proteins. Genome rearrangements are a hallmark of cancer and birth defects. To counteract the potential threat to the genome by DNA repeats, organisms have developed strategies to fight against the instability of DNA repeats. One strategy is to coat the repetitive sequences in protective proteins that prevent them from interacting with other repetitive sequences. This protective protein structure is called 'heterochromatin'. In fact, our DNA is packaged in proteins called histones - the DNA and histones together make 'chromatin'. The chromatin structure allows the DNA to be wrapped up so that it fits inside cells, and it also controls how often and how quickly the instructions coded by DNA are released to make proteins. Repeat sequences are packaged in specialised heterochromatin which is more tightly packaged in histones. This means that it's harder for repeats to find each other and harder for the proteins that might join up different parts of the genome to find the repeats. Therefore, heterochromatin acts to prevent genome rearrangements. For this reason it is important to know how DNA repeats are packaged into heterochromatin. This is one of the questions that we aim to answer in this proposal. We will study heterochromatin formation in a simple model organism, the unicellular yeast Schizosaccharomyces pombe. We study S. pombe because its heterochromatin is similar to what is found in humans but simpler. In S. pombe, we have recently developed systems to take apart and build up the process of heterochromatin assembly to understand how it is put together. Using this system we aim to identify the DNA sequences and the proteins that allow heterochromatin to be assembled and maintained on DNA repeats. For certain organisms, such as microbial pathogens, it could be convenient in certain environmental conditions to rearrange their genomes and therefore to temporarily erase heterochromatin from DNA repeats. One of such organism is the fungal pathogen Candida albicans. C. albicans is the most important human fungal pathogen. It normally lives inside our body without problem, but in certain situations (e.g. immunocompromised patients), it can cause life-threatening diseases. Pathogenic C. albicans adapts efficiently to different environments and it can acquire resistance to anti-fungal drugs. This is because, in contrast to most organisms, C. albicans can live and thrive without the normal, correct ratios of genes and even missing part of a chromosome (a phenomenon called genome plasticity). It was discovered that DNA repeats (called MRS) play an important role into the transformation of C. albicans into a dangerous pathogen. Rearrangements of the genome often occur at the MRS repeats. We will ask whether the MRS repeats are usually kept in a 'safe' state by being coated in heterochromatin and whether the type of chromatin at MRS changes to allow the genome rearrangements that cause C. albicans to become a pathogen. We will ask whether the type of chromatin at MRS repeats controls C. albicans pathogenicity.