Epigenetics involves biochemical changes in our bodies that directly impact our DNA, making some genes active, while silencing others. The current finding shows that a mechanism underlying one such epigenetic manoeuvre – ‘histone modification’ – appears to lock and unlock genes that prevent and trigger cancer.
Each cell in the body contains two metres of DNA, coiled tightly around tiny ‘nucleosomes’ (molecular structures made up of ‘histones’) in a configuration that resembles beads on a string.
That structure is then further compacted in a highly organised way to fit into the smallest space possible. Such tight compaction results in some genes being on the surface, so available for ‘expression’, while others are buried and ‘silent’.
Various normal developmental processes, as well as environmental factors (diet, stress, toxins) bring about small but critical changes in the way our DNA is arranged. Chemical compounds bond with DNA or histones, causing ‘methylation’ or ‘acetylation’ at specific sites, and literally reconfiguring the DNA structure.
Postdoctoral Fellow Dr Fatima Valdes-Mora and Professor Susan Clark, Head of the Epigenetics group at Sydney’s Garvan Institute of Medical Research, have identified a critical epigenetic change to a single histone when cancer develops. Four pairs of histones (H2A, H2B, H3 and H4) form each nucleosome, and they have demonstrated in prostate cancer that when one of the histones, a variant called H2A.Z, is acetylated, cancer genes are activated and tumour suppressor genes are silenced. Their findings are published in Genome Research, now online.
“This is a very important finding in the field of epigenetics – essentially providing a new conceptual paradigm,” said project leader Professor Susan Clark.
“In cancer, many genes become activated, and this paper is telling us that activation is directed by acetylation of a specific histone variant.”
“The acetylation of this histone variant opens up the DNA structure, allowing regulatory proteins to come in.”
“Conversely, tumour suppressor genes are normally active, and so acetylated. In cancer, they lose their acetylation and become inactive.”
“The key point here is that we’ve identified a histone variant and a new modification to histones that’s involved in the activation of oncogenes.”
Dr Fatima Valdes-Mora, who did much of the basic science and analysis on the project, is confident that the finding potentially provides a new diagnostic marker for cancer – as well as a novel therapeutic target for all cancers.
“While we have analysed only prostate cancer genomes in detail, and compared them with normal genomes, we believe our results will apply to all cancers,” said Valdes-Mora.
“There is still much basic science to be done before we can identify drug targets, as we still have to identify the enzyme that leads to this specific acetylation. That is the next step in our process.”
The Garvan Institute of Medical Research was founded in 1963. Initially a research department of St Vincent’s Hospital in Sydney, it is now one of Australia’s largest medical research institutions with over 500 scientists, students and support staff. Garvan’s main research programs are: Cancer, Diabetes & Obesity, Immunology and Inflammation and Neuroscience. Garvan’s mission is to make significant contributions to medical science that will change the directions of science and medicine and have major impacts on human health. The outcome of Garvan’s discoveries is the development of better methods of diagnosis, treatment, and ultimately, prevention of disease.
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