Friday 8 November 2019 4:38pm
Otago Biochemistry leaders of Marsden-funded research projects for 2019. From left, Dr Sarah Diermeier, Dr Paul Gardner, Dr Chris Brown, Dr Tanya Major (above), and Professor Tony Merriman.
Otago Biochemists are celebrating the results of the 2019 Marsden Fund applications this week, with five imaginative and exciting projects led by researchers in the Department of Biochemistry chosen for funding support.
The projects reflect the diverse range of research that goes on in the Department. From identifying new ways that bacteria stop gene expression, through to finding out why some living things have evolved more genes than others, and looking at the origins of high rates of metabolic disease in Māori and Pacifika populations, these projects encompass a wide range of research techniques and subjects, but are all united in that they are finding out how living things work at the molecular level.
The Marsden Fund is is the only source of research funding in New Zealand for ‘blue skies’ research, where scientists can work on projects that are led by scientific curiosity, and aimed at generating new knowledge. ‘Real-world’ uses for the research do not have to be immediately obvious, so scientists are allowed to be more creative with their research ideas.
The five funded projects are:
New ways of terminating bacterial gene expression
Project leader: Dr Chris Brown
Funding: $960,000 over three years
A comprehensive understanding of how bacteria control gene expression is important for determining how they cause disease, and provides antibiotic targets. Correct termination of transcription is a critical step in gene expression. In bacteria, there are two established termination mechanisms. However, our analysis of new genome-wide data, and our preliminary experimental data strongly suggest that transcription also terminates via one or more novel mechanisms. These mechanisms are likely to be more important in pathogens that lack one of the well-established mechanisms. We propose to investigate fully this novel way of stopping using a combination of bioinformatic, transcription assays, and genetic approaches in bacteria. Through this research, we expect to open up this new area of study, and potentially provide novel targets for antibiotics.
Walking backwards into the future: an evolutionary investigation into the high rates of metabolic disease in Pacific populations
Professor Tony Merriman (Department of Biochemistry, University of Otago)
Dr AL Gosling (Department of Anatomy, University of Otago)
Professor EA Matisoo-Smith (Department of Anatomy, University of Otago)
Associate Professor FA Camacho (University of Guam)
Dr PP Pumuye (University of Papua New Guinea)
Funding: $3,000,000 over three years
Māori and Pasifika populations are disproportionately affected by metabolic diseases such as diabetes, gout, obesity, renal and heart disease. Hyperuricaemia, or high levels of urate in the blood, is a unifying factor to many of these diseases. Several genetic markers associated with hyperuricaemia and metabolic disease have been identified in Polynesian populations. We hypothesise that this high rate of metabolic disease is associated with their Pacific ancestry (either deep or more recent ancestry) and that selection by infectious disease exposure, and particularly malaria, may have played an important role in shaping Pacific genomes, their tendency towards hyperuricaemia and thus metabolic disease. We will test these hypotheses through the strategically designed collection of new genome, biochemical and health data, from a range of Pacific populations with different settlement histories to Polynesia, and combine these with our existing data from New Zealand. We will investigate the Pacific-wide distribution of previously identified population-specific genetic markers associated with metabolic disease and, using the latest genomic and bioinformatics tools and modelling, determine how ancestry, selection, drift and admixture have shaped Pacific genomes. Finally, we will directly test the hypothesis that malaria may have played a role in selection for a hyperuricaemic phenotype.
Are molecular mis-interactions a major constraint on the evolution of cellular and genomic complexity?
Project Leader: Dr Paul Gardner
Funding: $960,000 over three years
Cellular genomes vary in size by six orders of magnitude. Bacteria can have genomes as tiny as 160 kilobases, whereas some plant genomes are as mighty as 150 gigabases. The large range of genome sizes, and the corresponding number of proteins and RNAs, leads to a combinatorial explosion of potential molecular mis-interactions in crowded cells. Recent theoretical research suggests that mis-interactions place major limits on protein and RNA sequence evolution, and selects for sequences that can avoid mis-interactions while still maintaining function. An efficient way to reduce the impact of mis-interactions is to compartmentalise cells. These compartments may have allowed the diversity of eukaryotes to increase and to exploit different environments. However, it is becoming apparent that many bacteria and viruses also use compartments. We hypothesise that subcellular compartments are essential for organisms to transition from small to large numbers of genes. We will test this hypothesis by identifying and characterising subcellular compartments from organisms covering a broad range of genome sizes and subcellular complexities. The best multi-disciplinary meta-analysis, bioinformatics, genetics and spatiotemporal cellular imaging techniques will be used to tackle this central question in evolutionary biology.
The role of epigenetics in the inappropriate activation of the innate immune system during gout flares
Project Leader: Dr Tanya Major
Funding: $300,000 over three years
Have you ever wondered why your sibling has a disease and you do not? Siblings share (roughly) half their genes, and are often raised in the same environment. So why does one brother develop gout and not the other?
Many diseases are complex, affected by both genes and environment. Gout is one of these diseases. It is an auto-inflammatory arthritis characterised by sudden flares of extreme, debilitating joint pain. Gout flares are a consequence of the innate immune system (your first defence against infection) inappropriately reacting to non-threatening environmental cues. Epigenetic chemical marks on genes can control the influence of environment on immune system responses. Epigenetic marks are removed or added to genes in response to environmental factors, changing the way these genes are controlled. Many of these factors trigger gout flares. Is the overlap between gout flare triggers and environmental influencers of epigenetic marks a coincidence?
We hypothesise that environmental factors are triggering gout flares through their influence on epigenetic control of the innate immune system. We will use state-of-the-art epigenomic tools to determine whether epigenetic marks play a major role in activation of the innate immune system, leading to gout flares in one brother, but not the other.
Assessing the molecular mechanism of a cytoplasmic long non-coding RNA
Project Leader: Dr Sarah Diermeier
Funding: $300,000 over three years
Genome-wide studies revealed the presence of up to 100,000 genes encoding for long non-coding RNAs (lncRNAs) in the human genome. More than half of all lncRNAs localise to the cytoplasm, but their functions and molecular mechanisms remain largely elusive. We recently identified 169 lncRNAs essential for cell viability in metastatic breast cancer, including many cytoplasmic transcripts. Here, we propose to study the molecular mechanism of the lncRNA lncTNBC1, a previously uncharacterized cytoplasmic lncRNA, which significantly impacts cancer cell growth. Based on our preliminary data on this tumour-specific molecule, we hypothesise that lncTNBC1 acts by binding to other RNA molecules in the cell, thereby modulating protein synthesis of essential cell growth regulators. Our results will contribute to unravelling new functions of cytoplasmic lncRNAs in the cell and their potential as new prognostic and/or therapeutic targets in cancer.