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New Mechanism for Gene Silencing Identified
Could give new targets for cancer therapies and production of stem cells
Tuesday, 5 August 2003

Frank J. Rauscher III, Ph.D. Photo by the courtesy of UPENN.

Humans are estimated to have between 30,000-70,000 genes, but in all 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 foetus. 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 tumour 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. But it also has implications for stem-cell research. If this mechanism of silencing genes involved in embryo development could be exploited, one could theoretically reverse the silencing and create stem cells.

"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.

"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 tumour formation. The hope is that, in a tumour, for instance, we could learn to re-silence these genes that are being aberrantly reactivated."

"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," Rauscher says.

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 de-acetylase 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.

More speculatively, Rauscher says that the study could also 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," he says. Rauscher stresses that for now this is strictly conjecture but that it seems scientifically possible.

What remains to be explored is how gene silencing is maintained during and after mitosis — or, to put it another way, how this gene silencing is inherited during cell division.

The research has appeared in the August issue of Genes & Development.

Source: Press release from The Wistar Institute, Thursday, July 31, 2003.
This article has been modified by CellNEWS from the above-mentioned source.