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Discovering novel pathways for gout via functional genetics (in collaboration with Prof Tony Merriman and Dr Megan Leask)

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 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 the Health Research Council of NZ.

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 are using multiple molecular approaches in leukaemia cells and a zebrafish in vivo model to determine how cohesin mutations lead to AML. We are also screening for drugs that selectively target cohesin-mutant leukaemias, and characterising their activity in human cells and zebrafish.

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

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 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 determine how cohesin activates genes for the first time in the developing embryo. 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.

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