About the Investigator:

Born in Israel, Dr. Cohen began his academic career at Ben-Gurion University where he received training in the field of molecular human genetics during his MSc and PhD studies. Next, he spent 5 years working on epigenetic regulation of skin development at the Icahn School of Medicine at Mount Sinai Medical Center, New York, USA. He is currently an Assistant Professor in the Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, at Ben-Gurion University of the Negev.

About the Research:

Every cell in the body contains the same collection of genes. Initially, these are inherited from parental sperm and egg, and then passed on to daughter cells, as the fertilized egg becomes an embryo and eventually an adult organism. If every cell contains the same genes, then how can liver cells be different from lung cells, which are different from cells of the skin and all other organ-specific cells? The answer lies in the realization that different genes are expressed (turned on) in different cells at different times in development: liver genes are on in liver cells, lung genes in lung cells, and so forth. Epigenetics is a mechanism by which chemical changes in DNA that do not affect its coding structure alter whether a gene is expressed or not.

In cancer, there are always severe and important alterations in gene expression, many of which arise because of epigenetic mechanisms. For example, in tissues where cells that generally do not divide, like skin, become cancerous, genes that inhibit cell division may not be expressed and genes that stimulate cell growth may be expressed. The Polycomb system functions in cells to make chemical changes in the DNA that safeguard cellular identity — those characteristics that distinguish one cell type from another. However, Polycomb activity is intricate and varies by cell type. There are two different repressive Polycomb complexes, Polycomb repressive complex 1 (or PRC1) and PRC2, which can operate together or separately through diverse mechanisms that can result in either gene repression or activation. Thus, different alterations in Polycomb subunits can lead to different and even opposing biological outcomes.

Loss of cell identity (the lack of characteristics typical of the fully mature cell type) occurs in all cancers, though little is known regarding how this happens. This proposal focuses on the role of PRC1 to modify a protein, histone H2AK119, that this laboratory was first to describe as inhibiting gene expression. Preliminary studies indicate that PRC1 modified H2AK119 silences the cancer-causing changes in human cutaneous squamous cell carcinoma (cSCC), a potentially life-threatening skin cancer. Using mouse skin as a model for PRC1 activity, these investigators will test whether increased PRC1 activity is therapeutic for cSCC and could serve as a drug target. The proposed research has broad implications for both basic and translational research and great potential for identifying new therapeutic targets or alternative treatment strategies for cancers.