A major breakthrough study, published today in Nature, has provided a complete roadmap of the human epigenome and has major implications for the treatment of human diseases and development of stem-cell based regenerative medicine.
An epigenome may be thought of as the clothes that dress a genome, controlling the way genes are packaged and expressed without actually altering the underlying DNA code.
Epigenomes are flexible and can be changed by environmental factors such as diet, stress and chemical exposure, leading to changes in gene expression. These changes can be temporary or they can be more permanent, with some studies suggesting they can be passed down from generation to generation.
Such epigenetic changes have been shown to account for clear physical differences between otherwise genetically identical organisms.
Epigenetic changes are essential because correct timing of gene expression is needed for healthy physical development and for the prevention of genetically based diseases such as cancer.
Conducted by an international consortium, including three researchers linked to The University of Western Australia (UWA), this is the first study to fully sequence the human epigenome at single-base resolution, and required re-sequencing the human genome more than 30 times to map the location of tens of millions of tiny biological markers, known as cytosine methylation sites.
The paper also reveals a remarkable difference between normal human cells and stem cells in the type and pattern of methylation sites. The stem cells contain many methylations at unusual sites in the genome that must be actively propagated from one cell division to another. This finding could provide the key to understanding how stem cells can make many different cell types, while other human cells have defined roles that cannot be changed.
The lead researcher in this groundbreaking study was Dr Ryan Lister, a former UWA plant scientist now based at the Salk Institute for Biological Studies in San Diego, California. UWA PhD student Julian Tonti-Filippini, supervised by UWA Professor Harvey Millar, collaborated with Dr Lister to develop software tools for data handling, analysis and visualisation.
This is the second collaboration between the three scientists, following a successful study that mapped the complete epigenome of the model plant Arabidopsis thaliana, published last year in the journal Cell.
"This study represents a remarkable advance for human biology and medical science," Professor Millar said. "It has been a truly international collaborative effort and we are very excited about the ground breaking possibilities that may occur as a result.
"Julian originally designed his software to better understand gene expression in plants but with some further development, it evolved into a set of tools for digitalising the human epigenetic code."
Graphic representations of epigenome and photographs of researchers Professor Harvey Millar and Mr Julian Tonti-Filippini (copyright: Paul Ricketts, DUIT Multimedia) are available.
Background - the consortium
This breakthrough study was conducted by a consortium of The Salk Institute for Biological Studies; Ludwig Institute for Cancer Research and University of California San Diego; Morgridge Institute for Research, the Genome Centre for Wisconsin and The University of Wisconsin-Madison; and The University of Western Australia.
It is part of, and funded by, the NIH Roadmap Reference Epigenome Consortium.
Both Mr Tonti-Filippini and Professor Millar work in the Australian Research Council-funded ARC Centre for Excellence in Plant Energy Biology and the WA Government-funded State Centre of Excellence in Computational Systems Biology at The University of Western Australia.
Background - epigenetics
Defining the sequence of the human genome was hoped by many to be the end of the puzzle of defining what humans are and to be an answer to curing diseases. But some years on it is clear many other factors can affect our genes and how they perform - such as environment, diet and exercise - through what is called ‘epigenetics'.
Epigenetics describes the modification to genes other than changes to the DNA sequence. These can be decorations on the DNA or differences in how tightly-packed the DNA is. These can turn genes on or off or up and down, like a switch. You can inherit them from your parents, and you can pass them on to your kids.
These epigenetic changes are a normal part of human development; however, if they go wrong it can affect health and cause disease. For example, turning off genes that protect cells or regulate metabolism can lead to cancer. Even conditions as varied as asthma and schizophrenia are influenced by epigenetics. Epigenetics is predicted to have more impact on the diseases of more humans than genetic differences.
To fully explore epigenetics, we needed a new map to supplement the genome, we needed the ‘map of the epigenome'. A key part of this is the need for a record of the tens of millions of tiny decorations, termed methylations, where they are on DNA and which genes they can influence. This is what has been achieved in this research - the first full methylome of humans.
Now we can understand not just what one epigenetic marks looks like but what the patterns are in the whole genome, and how they change during development and differentiation of cells.
Genetics we cannot really change, but methylation is reversible so medicines targeting methylations could help to cure epigenetic diseases in the future. But medical research is still at the very beginning of understanding how small numbers of the tens of millions of marks could be changed through gene-specific DNA modification enzymes.
What can we do with this map of the epigenome?
This ‘map' is a template for future studies by providing the first baseline, just like the human genome now provides a baseline for comparisons of human genomes from all over the world.
It shows many genes that are under epigenetic control that we did not know about, and the importance of different kinds of methylation and how they influence genes.
This template can help us design tests to screen for epigenetic diseases, because it points to where to look for changes. It can help researchers who are developing medicines to influence methylation and turn off cancer cells.
It is providing a new understanding of how stem cells are so unique and how they maintain their ability to become any cell in our bodies.
In the future, a person may have his or her genome sequenced to uncover genetic propensity to disease or highlight special potentials. But the epigenome could also be analysed to see the effect of a person's (or their parent's) environment or diet on which genes are tuned up or down through epigenetic marking.