Projects

Discovering novel pathways for gout via functional genetics (in collaboration with A/Prof Tony Merriman)

High levels of uric acid cause gout. Uric acid is made in the blood, and its levels are regulated by urinary excretion. Drugs that lower uric acid can prevent gout.

Genetic studies have identified approximately 30 reasonably precise, but not exact, areas of the human 'genome' (DNA) that control levels of uric acid. These regions are in non-protein coding DNA, and we think that they control the amount of protein made rather than how the proteins work. Understanding how these non-coding regions work could lead to new approaches for drug discovery.

We are using an innovative zebrafish readout system, and measurement of chromosome dynamics in cell lines, to discover how these genomic regions control the amounts proteins that contribute to urate levels.

The work is funded by an Explorer grant from the Health Research Council of NZ, and is a joint project with Assoc Prof Tony Merriman

Investigating a new drug target in acute myeloid leukaemia

It is rare to identify completely new genetic pathways that lead to cancer. However, the incentive to do so remains strong, to identify novel opportunities for therapeutics. Recent whole genome sequencing approaches have pinpointed mutations in genes that were previously not associated with cancer. For Acute Myeloid Leukaemia (AML) this approach revealed that 9-13% have mutations in genes encoding the chromosome cohesion complex, cohesin.

Cohesin mutations represent a new genetic pathway for AML, but how AML arises from these mutations is unknown. We found that cohesin regulates expression of a gene already well known to cause AML: RUNX1. We hypothesise that cohesin mutations cause AML by leading to abnormal RUNX1 expression.

First, we are testing this hypothesis using multiple molecular approaches in leukaemia cells and a zebrafish in vivo model. Second, we will screen for drugs that selectively target cohesin-mutant leukaemias, and characterise their activity in human cells and zebrafish.

The work is funded by a project grant from the Health Research Council of NZ.

A novel model for exploring the causes and treatment of craniofacial birth defects in children

Cleft lip and cleft palate are common craniofacial birth defects. The incidence of cleft lip and/or palate (CL/P) is 1/700, and treatment over a lifetime can be very costly. The general view is that clefts are caused by a combination of genetic and environmental factors.

In this research we want to determine how genetic and environmental causes of CL/P affect the growth and survival of cells contributing to the palate during embryo development. More importantly, we want to determine whether factors that enhance cell survival can actually rescue development of CL/P. The study is being done in zebrafish, an ideal animal model for these experiments.

Our research could identify a potential for treatment with antioxidants to prevent CL/P in children, especially in families where there is an identified genetic or environmental risk.

This work is funded by the NZ Dental Foundation and the Otago Medical Research Foundation.

Exploring the oncogenic potential of Rad21

In eukaryotic cells, sister chromatid cohesion is regulated by cohesin, a large multimeric protein complex. The Rad21 protein is a subunit of mitotic cohesin. Studies have shown that RAD21 is differentially regulated in cancers, and overexpression of RAD21 is associated with poor prognosis in breast cancer. We previously showed that cohesin positively regulates expression of the MYC oncogene (Rhodes et al., 2010; McEwan et al., 2012; Antony et al., 2015).

We are using the zebrafish animal model and cancer cell lines to investigate a role for cohesin in cancer through the regulation of gene expression.

Our results could provide important and novel insights into the development of cancer.

Investigating a developmental role for cohesin

A recently fertilised embryo contains rapidly dividing cells that have the potential to develop into any part of the body. One of life's biggest mysteries is how cells in the early embryo decide what to be. Cohesin proteins are essential for both chromosome duplication and for controlling expression of specific developmental genes. Cohesin also regulates genes that promote stem cell identity. Therefore, we hypothesise that cohesin forms a vital link between cell division and differentiation.

Mutations in cohesin proteins are associated with developmental defects and human syndromes, e.g. Cornelia de Lange syndrome. In this research project, we are using zebrafish to investigate cohesin and CTCF function during development, in particular, during stem cell commitment and zygotic genome activation.

AS part of this project, we are using high throughput sequencing to identify cohesin- and CTCF-bound genes pre- and post-zygotic genome activation. To find out if cohesin activates developmental genes in uncommitted cells, we are measuring expression of cohesin-bound genes during cell differentiation, and are determining if cohesin depletion changes their expression. The gene occupancy of cohesin will be aligned with other chromatin proteins signifying gene activation, or stem cell identity.

This work is supported by the Royal Society of NZ Marsden Fund.

Investigating oxidative stress and ageing using the zebrafish model

Organisms have adapted to the oxidising environments they live in through the ability to detect and respond to oxidative stress. Oxidative stress has a major impact on cells; reactive oxygen species are able to modify proteins, lipids, and DNA and initiate apoptosis. The phenotype of a developing organism is influenced by many environmental factors - it is possible oxidative stress may regulate developmental pathways.

In this project, we are using zebrafish as a model for researching the effects of oxidative stress during development and throughout adult life, including ageing. We hypothesise that zebrafish with cohesin mutant genetic backgrounds have impaired DNA repair pathways, and may respond differently to oxidative stress.

This work is being done in collaboration with Assoc Prof Mark Hampton at the Christchurch School of Medicine (mark.hampton@otago.ac.nz).

 

© Chromosome Structure & Development Group
Department of Pathology
Dunedin School of Medicine
PO Box 913
Dunedin
New Zealand

Tel 64 3 479 5509
Fax 64 3 479 5511
Email csdg@otago.ac.nz