Epigenetic regulation of DNA repeats and genome stability in Candida albicans

Candida albicans is an opportunistic fungus (a form of yeast) that normally lives on the human body without causing any harm. However, C. albicans can cause devastating diseases especially in immunocompromised patients who have undergone organ transplants, chemotherapy, or HIV treatment. 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 without the right proportion of its genes or even miss a part of a chromosome (a phenomenon called genome plasticity). It was discovered that rearrangements often occur at particular sites of repetitive DNA sequences. We want to understand why DNA repeats are sites of chromosome rearrangement.
In most organisms, DNA repeats 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 rearrange itself, 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 amount of proteins. Genome rearrangements are a hallmark of cancer cells 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'.
For certain organisms, such as microbial pathogens, it can be convenient in certain environmental conditions to rearrange their genomes and therefore to temporarily erase heterochromatin from DNA repeats. C. albicans could be one of these organisms and we will test this hypothesis. We will ask whether C. albicans DNA repeats are usually kept in a 'safe' state by being coated in heterochromatin and if C. albicans can strip these proteins off to allow the genome rearrangements in favourable conditions to cause C. albicans to become a pathogen.

C. albicans is the most prevalent human fungal pathogen. It normally lives as commensal in humans but, in certain environmental conditions, such as those found in immunocompromised patients, it can become virulent causing systemic life-threating diseases. Emergence of drug-resistant C. albicans strains poses an additional public health problem. C. albicans is a highly successful pathogen partly due to its remarkable genome plasticity. The C. albicans genome is relatively stable in normal laboratory growth conditions but it becomes unstable under stress conditions, such as an anti-fungal treatment.
Even though very little is known about mechanisms inducing C. albicans genome plasticity, it is clear that DNA repeats play an important role in this process. Our major goal is to understand the role of DNA repeats in modulating C. albicans genome plasticity.
In many organisms, genome stability at DNA repeats is ensured by the assembly of a heterochromatin structures inhibitory to recombination. The chromatin status associated with C. albicans DNA repeats is uncharacterised and it is unknown whether it contributes to genome stability. In this project, we will employ a combination of low-throughput and high-throughput approaches to determine the chromatin state associated with C. albicans DNA repeats and assess the role of chromatin in C. albicans genome plasticity upon environmental changes.

Who will benefit from this research?
This is basic research in nature but it tackles questions which can find applications beneficial to areas of health and wealth. Academia will be the most direct sector to benefit by the research since the proposed work relate to scientific and knowledge advancement. The research disciplines which will most benefit are the ones related with microbiology, infectious diseases and epigenetics. In the longer term, this research has the potential to impact in areas of healthcare and pharmaceutical industries. Beneficiaries beyond academia are the biopharmaceutical sector with interest in anti-fungal drug discovery and the wider general public.

How will they benefit from this research?
The Bioscience research community.
Chromatin biology in the fungal pathogen Candida albicans is a surprisingly poorly explored area. Our research will generate data and knowledge on this area of research that will benefit the whole C. albicans community and those interested in fungal biology. This project will also deliver increased capacity and capability in this area of biology through the provision of training and further development of key methodologies. Scientists interested in epigenetics and global regulation of gene expression will benefit from our discoveries of mechanisms underlying modulation and propagation of chromatin domain at DNA repeats under different environmental conditions.

The biopharmaceutical sector with interest in anti-fungal drug discovery.
C. albicans is the main human fungal pathogen. One of the major obstacles in defeating this pathogen is the high occurrence of anti-fungal drug resistance, creating an urgent need for innovative anti-fungal drugs. Our research will unveil epigenetic mechanisms regulating C. albicans genome stability and pathogenicity and will have the potential to identify new anti-fungal targets. This research in this proposal could potentially be exploited for commercial applications.

The wider general public.
C. albicans infection is at the basis of important life-threating diseases with mortality rates up to 50%. These diseases have huge cost implications and our research, in the longer term, will benefit the National Health Service, the patient and ultimately the UK economy by the development of new drugs.

In synthesis, our research will provide substantial and widespread benefit to our society with respect to scientific output, the economy, quality of life and health.