In a just-completed study, two collaborating groups of scientists at The Wistar Institute have identified the structure of a molecule known to regulate gene expression. The molecule, called Esa1, is essential for cell growth in yeast and is related to a human molecule that has been implicated in certain forms of leukemia.
The scientists also compared this new structure with that of several molecules with related function but dissimilar composition. The comparison revealed unanticipated structural similarities, suggesting the molecules likely share a common mode of action, whatever their chemical dissimilarities. The new findings are reported in the November issue of Molecular Cell, to be published November 17.
The ability to turn genes on and off appropriately is key to normal function in all cells, and mutations in the regulatory molecules studied have been linked to an array of diseases, including cancers. The finding that these molecules, known as histone acetyltransferases, or HATs, share important structural features and perhaps a unified mechanism of action highlights the potential value of any anti-cancer drugs that would target this mechanism.
"These molecules help balance the activation and inactivation of genes in the cell in a way that appears to be crucial to health," says Ronen Marmorstein, Ph.D., senior author on the study and an associate professor at The Wistar Institute. "When they are disrupted, disease states such as cancer can result. So, the development of drugs to modify their activity, perhaps based on structural insights, could have significant medical implications."
The study used X-ray crystallography to obtain the structures of the molecules, a much more demanding analytical technique than, for example, DNA-sequence comparisons. But the use of the more strenuous approach proved pivotal.
"We couldn't have anticipated the structural similarities among these molecules from their genetic sequences," says Shelley L. Berger, Ph.D., a co-author on the study and an associate professor at The Wistar Institute. "We needed the structural comparisons to come to the conclusions we came to."
Scientists have only recently begun to fully appreciate the role played by histone acetyltransferases in promoting gene expression. They work in coordination with a related group of regulatory molecules called histone deacetylases, which inhibit the expression of genes.
Both act on histones, which are small proteins around which DNA coils itself to form structures called nucleosomes. Compact strings of nucleosomes, then, form into chromosomes, of which humans have 23 pairs in the nucleus of every cell. When the DNA is tightly wrapped around the histones, the genes cannot be accessed and their expression is repressed. When the DNA coils around the histones are loosened, the genes become available for expression.
Although scientists have yet to fully illuminate the process, they know that histone acetyltransferases add an acetyl molecule to a tail-like structure on the histones, which has the effect of loosening the DNA coils. Histone deacetylases remove an acetyl molecule from the histone tails, causing the DNA to wrap more tightly around the histones. The molecules compared by the Wistar researchers come from the MYST, Gcn5/PCAF, and Hat1 families of histone acetyltransferases, with Esa1 being a member of the MYST family.
The lead author on the study is Yuan Yan, B.S. In addition to Marmorstein and Berger, the other co-authors are Nickolai A. Barlev, Ph.D., and Randall H. Haley, B.S. Funding for the work came from the National Institutes of Health.
The Wistar Institute is an independent nonprofit biomedical research institution dedicated to discovering the basic mechanisms underlying major diseases, including cancer and AIDS, and to developing fundamentally new strategies to prevent or treat them. The Institute is a National Cancer Institute-designated Cancer Center - one of the nation's first, funded continuously since 1968, and one of only ten focused on basic research. Founded in 1892, Wistar was the first institution of its kind devoted to medical research and training in the nation. News releases from The Wistar Institute are available to reporters by direct e-mail or fax upon request. They are also posted electronically to Wistar's home page (http://www.wistar.upenn.edu), to EurekAlert! (http://www.eurekalert.org), an Internet resource sponsored by the American Association for the Advancement of Science, and to the public interest newswire AScribe (http://www.ascribe.org).
Journal
Molecular Cell