New Mechanism for Essential Genome-Wide Gene Silencing Identified

(PHILADELPHIA – April 14, 2006) – Most of the time in most cells of the body, the great majority of genes are silenced, locked away within the compacted but orderly material that makes up chromosomes. Estimates are that only about 10 percent of the roughly 25,000 genes in the human genome are activated, or “on,” at any given time in a particular cell – the default setting for most genes is “off,” or repressed.

Reliable gene silencing is vital to the health of an organism. Improperly activated genes can and do lead to cancer, for example. Gene silencing is also thought to protect the genome from viruses and other potentially damaging entities, thus preserving genetic integrity.

In a new study, researchers at The Wistar Institute and colleagues have identified an important new global mechanism for this essential gene silencing, or gene repression. A report on the findings appears in the April 15 issue of Genes & Development.

“We’ve discovered what looks to be an evolutionarily ancient mechanism for broadly repressing and protecting the genome,” says Shelley L. Berger, Ph.D., the Hilary Koprowski Professor at The Wistar Institute and senior author on the study. “We believe it to be the first identified mechanism of its kind.”

The new mechanism centers on histones, relatively small proteins around which DNA is coiled to create structures called nucleosomes. Compact strings of nucleosomes, then, form into chromatin, the substructure of chromosomes.

In the study, conducted in a type of yeast called Saccharomyces cerevisiae, the scientists showed that a protein called SUMO binds to histones and acts to repress transcription of genes, and it does so at many different sites across the genome. While several other histone-related mechanisms have been identified for activating genes in yeast, this is the first one recognized as repressing gene transcription.

The finding is significant because gene-regulation strategies first observed yeast and other lower-order organisms are often found in mammalian cells also, including humans. In an indication of their fundamental nature, critical genetic systems are frequently conserved with few changes in life forms that diverged during evolution millions of years ago.

“In our experiments, we saw SUMO binding to histones across the genome, suggesting that if this mechanism went wrong, it could have a dramatic effect,” says Berger. “We know, for example, that histones are important in a number of cancers, and SUMO may be a significant part of that.”

The research team also noted a dynamic interplay between the addition of a SUMO protein to a histone – sumoylation – and the addition of either an acetyl group or a ubiquitin protein to a histone. The processes appear to be mutually exclusive.

“Acetylation and ubiquitylation have both been shown in earlier studies to activate gene expression,” says Kristin Ingvarsdottir, co-lead author on the Genes & Development study. “Sumoylation, on the other hand, is involved in gene repression, so it makes sense that it might exist in an either/or relationship with acetylation or ubiquitylation.”

Another observation made during the study was that slightly higher levels of sumoylation occur near the tips of the chromosomes, the telomeres, which are known to play a central role in maintaining genomic stability. Instability in the telomeres has been linked to aging in humans and an elevated risk for aging-related diseases, the most prominent of which is cancer.

Sharing lead author credit with Ingvarsdottir is Dafna Nathan. With Ingvarsdottir, Nathan, and senior author Berger, the other Wistar-based co-authors on the study are David E. Sterner, Jean A. Dorsey, and Kelly A. Whelan. The additional co-authors are Gwendolyn R. Bylebyl and Erica S. Johnson at Thomas Jefferson University; Milos Dokmanovic, Mihajlo Krsmanovic, and Pamela B. Meluh at The Johns Hopkins University School of Medicine; and William S. Lane at Harvard University. Support for the research was provided by the National Institutes of Health.

The Wistar Institute is an independent nonprofit biomedical research institution dedicated to discovering the causes of and cures for major diseases, including cancer, cardiovascular disease, autoimmune disorders, and infectious diseases, including AIDS and influenza. 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 focused on basic and translational research. Discoveries at Wistar have led to the creation of vaccines for such diseases as rabies, rubella, and rotavirus; significant insights into the mechanisms of skin, brain, breast, lung, and prostate cancers; and the development of monoclonal antibodies and other significant research technologies and tools.

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