International Team of Researchers Develops New Tool to Elucidate the Epigenome

Technology has potential application for personalized cancer therapies

MILAN, ITALY — March 24, 2009 — An innovative technology for the rapid and reliable screening of the human epigenome (the set of functional DNA elements that regulate gene state and activity) is being developed by an international team of scientists at the IFOM-IEO Campus in Milan, in collaboration with a group from the J. Craig Venter Institute led by Samuel Levy, Ph.D., and a team from Sangamo BioSciences, Inc., led by Fyodor Urnov. The technology provides a new tool for disease diagnosis, and for the development of personalised cancer therapies. The research was published today in the international journal Developmental Cell.

This study falls within the scope of epigenetic research, an important branch of molecular biology that focuses on the mechanisms regulating gene expression and how alteration of these processes can lead to diseases such as cancer. The new experimental method employs high-throughput DNA sequencing technologies to rapidly identify the "active" DNA in a given cell type.The groups' research allows the epigenetic profiling of patients in three to four days, using only a small sample of cells.

A recent, but increasingly accepted idea among the international scientific community, is that the majority of cancers are caused by alterations, not only at the genetic level (i.e. mutations in the DNA sequence), but also at the epigenetic level, thus altering mechanisms that regulate gene expression. Epigenetic research is becoming an important field of molecular research that complements genetic research and holds very promising prospects for the development of new therapies; epigenetic alterations, unlike genetic mutations, can be efficiently reversed using pharmacological approaches, making it more feasible to design therapeutic interventions that target epigenetic alterations.

The technology, under development at the IFOM-IEO Campus in Milan which is one of the most prominent international centers for epigenetic research, provides a new tool for screening epigenetic alterations and opens promising avenues for disease diagnosis and for the development of therapies targeting these alterations.

"In the near future we will be able to rapidly and reliably obtain the epigenomic profile of patients, adding a new dimension to molecular diagnosis of diseases, and to the identification of personalised therapies," said Saverio Minucci, Director of the Chromatin Alterations in Tumorigenesis Programme at IEO's Department of Experimental Oncology, based at the IFOM-IEO Campus in Milan, and Associate Professor of General Pathology at the Department of Biomolecular Sciences and Biotechnology at the University of Milan.

The test is performed using a very small sample of human cells. "We use around one million cells and samples of this size can be easily obtained from the patients," explains Gaetano Gargiulo, first author of the paper. "With our test we can obtain highly reliable results (90% accuracy in prediction of the epigenetic state) with relatively few cells, while similar technologies presently under development give results that are consistently less accurate and require much larger amounts of sample which are limiting for diagnostic applications," said Gargiulo.

The epigenomic screen employs precise experimental manipulations using restriction enzymes that cut regulatory DNA in a defined manner. The result of this excision process is then further purified via a novel modification of a high throughput sequencing process on the Roche 454. "In practice, the combination of the restriction enzyme treatment with a subtly modified 454 sequencing approach is sufficient to provide an unbiased screen of the human epigenome," added Samuel Levy, the Director of Human Genomics at JCVI.

Currently the test is being conducted on healthy individuals to map the epigenetic profile of normal cells. The next step will be to test cancer patients to systematically identify epigenetic alterations that are involved in cancer.

This research was made possible with support from AIRC (the Italian Association for Cancer Research), the EPITRON (Epigenetic Treatment of Neoplastic diseases) research project financed by the European Community, MIS (Italian Ministry of Health) and MIUR (Italian Ministry of Education, University and Research).

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