‘There are three billion base pairs of DNA in each cell. If you were to pull it out end to end, it would equal two metres of DNA, which has to fit inside the 3D nucleus of every cell in our body.’
We can now sequence DNA and read the order of the three billion bases but understanding how the genome is interpreted in its 3D context will be the next eureka moment.
‘The answer is in our epigenome. ‘Epi’ means the information above our genome that provides a different context or different clothing to the DNA in each cell type in our body,’ Professor Susan Clark said.
Australia is at the forefront of genomics research with Professor Susan Clark as our ‘epi’genome pioneer. She was one of the early scientists to read the DNA sequence in her PhD studies. Since then she has turned her attention to understanding how gene regulation is modified by epigenetics in 3D to control how cells function.
‘Epigenetics involves the chemical modification of the DNA, called DNA methylation, and chemical modifications of proteins, called histones, that the DNA is wrapped around. It is a combination of DNA methylation and histone modification that controls how our genes are expressed inside the nucleus,’ Professor Clark said.
‘The epigenetic patterns on top of the DNA can determine which genes are switched off and on. Therefore different types of cells have different epigenetic patterns, or different epigenomes.
‘We are no longer just reading the DNA sequence or DNA blueprint but we can now create 3D epigenome maps to begin to understand how the DNA blueprint is organised to determine normal cell function as well as how it is disrupted in diseased cells, such as in cancer.
‘This new understanding of how the cell works gives us exciting opportunities to design novel drugs to target the epigenome. New therapies, called epigenetic therapy, alter gene expression patterns without altering the DNA, and are now being trialled in cancer treatments,’ she explained.
The next challenge in epigenome research is to interpret and discover new modes of DNA biology that had previously never been imagined. This requires looking at the gene, the chemical and protein modifications of that gene and how these interact across the entire genome in a 3D context.
‘If you think about the epigenome as origami—our DNA is a piece of paper, with each fold creating a different gene set to be activated to eventually create a unique 3D shape or pattern. Each cell type will have its own unique 3D DNA shape that defines its function. If one of these folds is missing or incorrect the whole cell pattern will be changed and this can results in diseases such as cancer,’ she explained.
‘The bioinformatics interpretation of epigenome sequencing data is phenomenal. There are different types of sequencing datasets for each cell type. We are developing new technologies as well as using new bioinformatics tools to interrogate and interpret all this information.
‘Our big audacious goal is to understand these processes to ultimately prevent susceptibility to diseases such as cancer, and diseases that initiate during early development that may also have a major epigenetic component.’
Professor Clark was featured in NHMRC’s Ten of the Best 2009 publication for her research into epigenetic variation in early human development. Since then she has been awarded a number of NHMRC Project Grants and Research Fellowships, which allows her to continue to make these discoveries in molecular biology no one could have predicted.
‘NHMRC funding has allowed us to be and stay on the cutting edge of advances in basic research. Basic research is pivotal to great discoveries and our limited understanding of the epigenome has already made a huge difference to challenge conventional genomic thinking,’ she said.
‘It has also allowed us to be ahead of the world in developing new epigenetic sequencing technologies. Since I started my career, we have gone from taking three years to sequence 1000 base pairs of DNA in the late 1970s to today taking 48 hours to sequence the entire three billion base pairs of the genome and starting to understand the 3D context in different cell types. We have also been able to collaborate with a range of talented scientists nationally and internationally to make a difference we could not have even dreamt of on our own.’