Dr Catherine Suter

Research Focus:

Epigenetic gene regulation is important for a wide variety of vital biological processes. Epigenetic modifications allow cells with precisely the same genotypes to display a multitude of phenotypes; epigenetic gene regulation is therefore fundamental to the existence of all multicellular organisms. There is an increasing awareness of the role that epigenetics plays in human health and disease. The VCCRI's Epigenetics laboratory is interested in the role of epigenetic gene regulation in phenotypic variation and in disease, and in investigating the impact of early environmental perturbations on epigenotype and epigenetic inheritance.

Our present understanding of epigenetics could be likened to our understanding of genetics around a century ago ? its importance is recognised, but its mechanisms remain largely obscure. But with emerging genomic technologies becoming quickly adapted to interrogate the epigenome, now is an exciting and fast-paced time to be engaged in epigenetics research. Our studies rely heavily on the assessment of the most well characterized epigenetic mark, DNA methylation, primarily because we are interested in stable, and potentially heritable, epigenetic silencing. Over the last few years we have made some significant contributions to the field, and we currently have these ongoing areas of study:

Germline epimutation and disease risk

When the complex and fine-tuned processes of epigenetic silencing go awry, aberrant epigenetic silencing of a gene (epimutation) can occur.

In 2004 we discovered that epimutation could occur to a locus in the human germline and predispose to disease. We identified individuals with soma-wide epigenetic silencing of the tumour suppressor MLH1 predisposing them to develop multiple tumours. There are now dozens of such individuals reported in the literature, including several who had passed the epimutation on to offspring in the nonmendelian pattern typical of epigenetic phenomena.

The individuals that we and others have described appear to carry the epimutation in most or all of their somatic cells (implying a germline event), but epigenetic phenomena can revert, and thus are commonly mosaic, which raises important questions: are there some individuals who carry an epimutation in a small proportion of their cells, and how does this relate to disease risk? We are currently investigating this hypothesis as it relates to cancer predisposition in large cohorts of affected and unaffected individuals in collaboration with several clinical teams across Australia. 

Effects of early nutrition on somatic and germline epigenetic states

It is well known that environmental factors can influence health: some environmental insults, particularly those inflicted during embryonic development, can have adverse health effects lasting throughout life and even into future generations. But how might the environment encountered in gestation influence our makeup so that health effects are not felt until many years later?

Epigenetics provides an interface between our genes and the environment. Environmental changes that occur during gestational development can affect epigenetic states to modulate disease risk in adult life. In 2006 we used the Avy mouse model to demonstrate that a transient change in early nutrition, in the form of gestational methyl-donor supplementation, can alter the germline epigenetic state of a locus.

We are currently investigating the epigenetic consequences of multigenerational methyl-donor supplementation, and other nutritional stressors, on Avy and other loci in the genome.  These experiments involve mouse models and massively-parallel sequencing‑based epigenomic profiling.

The role of small RNAs in epigenetic disease and epigenetic inheritance

There is now little doubt that small RNA species play an integral role in the establishment and maintenance of normal epigenetic states. We are currently investigating the role of specific classes of small RNA in establishing aberrant epigenetic silencing such as that seen in cancer.

Emerging evidence also suggests that RNA may not only mediate epigenetic processes within cells, but perhaps also between cells, and possibly even between generations. Using mice and deep-sequencing technology, we are exploring the idea that RNA is the "substance" of epigenetic inheritance in mammals.  

Co-Investigators:

Dr Jennifer Cropley, PhD
Dr Michelle Holland, PhD
Paul Young, BSc, MSc (research officer)
Laura Molloy BSc (Hons) (research assistant)
Cheryl Li BSc (Hons) (graduate student)
Simon Keam BSc (Hons) (graduate student)
Andreas Adler (intern student)

Collaborators:
Professor David Martin, Children's Hospital Oakland Research Institute, USA
Professor Rob Martienssen, Cold Spring Harbor Laboratories, USA
Professors John Thompson and Richard Scolyer, Sydney Melanoma Unit, Australia
A/Professor Graeme Mann, Westmead Millennium Institute, Australia
A/Professor Thomas Preiss, Victor Chang Cardiac Research Institute
Professor John Rasko, Centenary Institute, Australia
Professor Alan Cooper, University of Adelaide, Australia
Professor Caroline McMillen, University of South Australia
Professor Roger Reddel, Children?s Medical Research Institute, Westmead, Australia

Selected Publications:
Ng, LJ, Cropley, JE, Pickett, HA, Reddel, RR, Suter, CM. Telomerase activity is associated with an increase in DNA methylation at the proximal subtelomere and a reduction in telomeric transcription. Nucleic Acids Research 2009; 37(4):1152-9.
 
Cropley, JE, Martin, DIK, Suter, CM. Germline epimutation in humans.  Pharmacogenomics 2008;(12): 1861-1868.

Martin DI, Cropley JE and Suter CM. Environmental influence on epigenetic inheritance at the Avy allele. Nutr Rev 2008;66 Suppl 1:S12-4.

Hitchins M, Wong JJL, Suthers G, Suter CM, Martin DIK, Hawkins NJ, Ward RL. Inheritance of a cancer-associated MLH1 germ-line epimutation. N Engl J Med 2007; 356(7):697-705. 

Cropley JE, Suter CM, Beckman KB, Martin DIK. From The Cover: Germ-line epigenetic modification of the murine Avy allele by nutritional supplementation.  Proc Natl Acad Sci USA 2006; 103(46):17308-12.

Suter CM, Martin DIK, Ward RL. Germline epimutation of MLH1 in individuals with multiple cancers. Nat Genet 2004; 36(5):497-501.

Bariol C*, Suter CM*, Cheong K, Ku SL, Meagher A, Hawkins N, Ward R. The relationship between hypomethylation and CpG island methylation in colorectal neoplasia. Am J Pathol 2003; 162(4):1361-71. (*Bariol C, Suter CM; co-first authors)

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