A History of the Australasian Epigenetics Alliance

The birth of epigenetics

The term epigenetics was coined and the concept of an epigenetic landscape was first proposed by Conrad Waddington (UK) in the 1940s and 1950s, but a molecular mechanism for epigenetic control of gene expression was not proposed until much later. In 1975, scientists working in England (John Pugh and Robin Holliday) and America (Arthur Riggs) independently suggested that methylation, a chemical modification of DNA, could alter the genetic program in response to environmental factors. This idea rapidly took root in the scientific community; however, the field experienced a major set-back in the 1980s when it was discovered that key model organisms used to study genetic regulation (Drosophila melanogaster and Caenorhabditis elegans) do not have DNA methylation.

The importance of epigenetics in mammalian gene regulation was not appreciated until 1992, when researchers working in America (En Li, Tim Bestor and Rudolph Jaenisch) reported that DNA methylation was essential for embryonic development in mice. At the same time, Marianne Frommer and Sue Clark (at CSIRO, Sydney, Australia) were developing a sequencing method to measure cytosine methylation at individual base pair and single molecule resolution. This resulted in an uptick in research across the globe, and by the mid to late 1990s, the roles of epigenetics in embryology, development, human disease and many other aspects of biology, were unravelling. Genomic imprinting, X-chromosome inactivation, transgene silencing in plants, histone modifications and chromatin remodelling were being investigated, and the significant role of DNA methylation in gene regulation was beginning to be revealed.

Forming Methylation Matters (1990s)

In the mid-1990s, interest in epigenetics was also on the rise across Australia, and a small number of epigenetics researchers from diverse fields of biology began discussing their work with each other.

At the time, Sue Clark was at the Kanematsu Institute, Royal Prince Alfred Hospital and CSIRO, NSW, and was using bisulphite sequencing for the first methylation sequencing studies in early development and imprinting in mice; and Emma Whitelaw was studying chromatin structure and epigenetic inheritance in mice at University of Sydney; and in CSIRO in Canberra, Jean Finnegan and Liz Dennis were researching DNA methyltransferases and DNA methylation patterns in plants.

Together with others from NSW and ACT, they began biannual meetings aptly termed Methylation Matters to share their research.

Around that time, Jean Finnegan observed a distinct increase in DNA methylation research at overseas scientific meetings, and how the emerging field of epigenetics was bringing plant and animal biologists together.

“Up until then, plant and animal researchers didn’t really mix much, but DNA methylation and other epigenetics studies brought them into the same rooms at meetings; epigenetic mechanisms were very relevant to both fields”

- Jean Finnegan

In 1994, Jean organised Australia’s first international conference on DNA methylation, at Thredbo, NSW. The role of DNA methylation in biological processes, a Boden conference, was run by the Australian Academy of Science and supported by ASBMB. The speakers included Tim Bestor, who was researching DNA methylation in mammalian development at Colombia University, USA, and Eric Richards, who was working on methylation in plant models at Washington University, USA.

 This was the same year, Sue Clark and Marianne Frommer published their work on their novel technology for DNA methylation analysis that could detect every methylated cytosine on both strands of any target sequence, using DNA isolated from fewer than 100 cells—bisulphite sequencing.

The Methylation Matters group headed by Sue Clark, supported by CSIRO, held its first national epigenetics meeting at Heron Island, QLD in 1996, with the first workshop on bisulphite sequencing and included international leaders in the field: Art Riggs (USA), Robin Holliday (Australia), Peter Jones (USA), Thomas Lindahl (UK- went on to win the Nobel Prize in Medicine 2015), Toshikazu Ushijima (Japan).

Heron Island 1996 meeting.

This photo was provided by Sue Clark (front, left). Including Art Riggs, Robin Holliday, Peter Jones, Thomas Lindahl, Geoff Grigg, Horace Drew, Toshikazu Ushijima, Peter Molloy

Meanwhile, discussions and workshops were taking place in the US about developing a blueprint for a human epigenome project. Sue Clark was involved in the early stages of what was to become the International Human Epigenetics Consortium (IHEC), and recognised the importance of Australia playing a role (Nature 2008; PMID: 18685699). Sue hoped to develop Methylation Matters into a nation-wide epigenetics association to showcase Australia’s role in this growing arena.

In the early 2000s, at MCRI in Victoria, Jeff Craig and Richard Saffery were studying human centromeres—Jeff was investigating epigenetic influences on centromere function, while Richard Saffery was researching centromeric chromatin remodelling in early development. In ACT, David Tremethick was working on histone variants and chromatin organisation at ANU; in NSW, Peter Molloy was studying DNA methylation as a biomarker in prostate cancer at CSIRO and Catherine Suter was investigating germline epimutation in humans at Victor Chang; and across the country in Perth, David Ravine was working on polycystic kidney disease and Rett syndrome at UWA. 

Thankfully, these great minds began coming together. Lorne Genome events were a good catalyst for this – at Lorne Genome 2003, Methylation Matters was showcased to a broader gene regulation community.