New Mechanism for Gene Silencing Identified

New Mechanism for Gene Silencing Identified

April 30, 2003

(PHILADELPHIA-Thursday, July 31, 2003)-Humans are estimated to have some 30,000-70,000 genes, but in any one of the body's many cell types, most of these genes are turned off, or silenced, appropriately prevented from doing their work of protein production. For example, there are thousands of genes that are active only during embryo development, their sole purpose to give rise to a perfectly formed fetus. These genes are found in every cell of the body but remain silent in healthy adults. Scientists have learned, however, that in many human cancers these genes associated with embryogenesis are inappropriately reactivated, causing the explosion of uncoordinated cell growth that is the hallmark of tumor formation.

Now, researchers at The Wistar Institute have identified a mechanism by which genes associated with embryogenesis are kept silent. Importantly, the silencing is heritable; that is, when a cell divides, its daughter cells maintain not only copies of its DNA but also the silencing of these genes involved in embryogenesis. Knowledge of this mechanism could lead to new cancer therapies aimed at re-silencing inappropriately activated genes. The research appears in tomorrow's print edition of Genes & Development and is featured on the journal's cover.

"The next great challenge for scientists studying the genome is determining how the genes in every cell of our body are regulated," says Frank J. Rauscher III, Ph.D., professor, deputy director of the Wistar Cancer Center, and associate director of research programs at The Wistar Institute. Rauscher is senior author of the study. "We know certain genes have to be activated in skin, for example, and silenced in the heart, liver, and other organs. The concept of the so-called epigenome-that is, how genes are either activated or repressed-will be critical to furthering our understanding of cancer and other diseases."

"In this study," Rauscher continues, "we've discovered a new mechanism involving multiple enzymes that keep these genes silent in healthy adults but active during critical times of embryonic development. Moreover, it appears that this silencing mechanism is clearly lost during tumor formation. The hope is that, in a tumor, for instance, we could learn to re-silence these genes that are being aberrantly reactivated."

When a gene is silenced, it is securely stored away in the tightly coiled structure of chromatin, which makes up chromosomes. Inside the chromatin, the DNA is wound around small proteins called histones, making it unavailable to the cellular machinery that would otherwise read its coded genetic information. The silencing mechanism that Rauscher's research team discovered is a precise multi-step process that involves histone modifications that result in gene silencing. First, a type of protein called a zinc-finger protein binds to the gene that is to be silenced. Then, sequentially, enzymes are recruited to the gene: First a histone deacetylase and then a histone methylase make specific changes to the histones. Finally, a protein called heterochromatin protein 1 (HP1) binds both to the gene and the histone, resulting in gene silencing.

Rauscher says that the identification of this mechanism should be useful in developing new cancer therapies. "From the standpoint of drug development, if you can get gene silencing down to a set of enzymes, which we have now, these enzymes should be relatively easy to target with drugs," he says.

What remains for Rauscher and other researchers to explore is how gene silencing is maintained during and after mitosis-or, to put it another way, how this gene silencing is heritable during cell division.

More speculatively, Rauscher says that the study could have implications for scientists interested in stem-cell research. "If we could learn to harness this mechanism of silencing these genes involved in embryo development, you could theoretically take a cell from any tissue type, reverse the silencing of these genes and create a population of cells that have a high probability of being stem cells," Rauscher says. He stresses that for now this is strictly conjecture but that it seems scientifically possible.

Along with senior author Rauscher, the additional Wistar scientists on the study are lead author Kasirajan Ayyanathan, Ph.D. and co-author Gerd G. Maul, Ph.D., professor in the Gene Expression and Regulation Program at Wistar. Co-authors at other institutions include Mark S. Lechner, Ph.D., of Drexel University, Peter Bell, Ph.D., of the University of Pennsylvania, and David C. Schultz, Ph.D., of Case Western Reserve University, all three of whom were formerly at The Wistar Institute; and Yoshihiko Yamada, Kazuhiro Tanaka, and Kiyoyuki Torigoe, all of the National Institute of Dental & Craniofacial Research at the National Institutes of Health.

Funding for the research was provided by the National Institutes of Health, the Department of Defense Breast Cancer Program, the Irving A. Hansen Memorial Foundation, the Susan G. Komen Breast Cancer Foundation, the Emerald Foundation, and the Commonwealth Universal Research Enhancement Program, Pennsylvania Department of Health.

The Wistar Institute is an independent nonprofit biomedical research institution dedicated to discovering the causes and cures for major diseases, including cancer, cardiovascular disease, autoimmune disorders, and infectious diseases. Founded in 1892 as the first institution of its kind in the nation, The Wistar Institute today is a National Cancer Institute-designated Cancer Center - one of only eight focused on basic research. Discoveries at Wistar have led to the development of vaccines for such diseases as rabies and rubella, the identification of genes associated with breast, lung, and prostate cancer, and the development of monoclonal antibodies and other significant research technologies and tools.