Wistar Study Offers New Support for a "Histone Code" Theory of Gene Regulation

Wistar Study Offers New Support for a "Histone Code" Theory of Gene Regulation

August 8, 2001

(PHILADELPHIA- August 9, 2001)—A new study by researchers at The Wistar Institute provides important experimental data to support a novel theory of gene regulation. The theory holds that coordinated patterns of modifications to DNA-packaging proteins called histones may be a key factor in turning specific genes on or off.

The proposed system of gene control has been termed a kind of "histone code" by one researcher and may govern most gene activity. Understanding the system could well prove crucial to researchers exploring cancer, developmental disorders, and other disease processes that hinge on gene control gone awry.

In their study, the Wistar scientists identified an enzyme that works in concert with another enzyme to modify a histone, triggering the transcription of a particular gene in yeast. The findings represent one of the first times that two modifications of a histone, one dependent on the other, have been shown to be necessary for a gene's activation. A report on the work appears in the August 10 issue of Science.

"The linking of this pair of histone modifications to the transcription of a gene strongly supports the notion that a kind of intricate interplay among such alterations a code, if you will may be controlling the greater part of gene activity," says Shelley L. Berger, Ph.D., an associate professor and senior author on the study. "Scientists are just beginning to explore this system of gene regulation. Already, however, it looks as though it may of comparable importance to the discovery some years ago of activator and repressor molecules that bind directly to DNA to turn genes on or off."

Estimates are that only a tenth of all human genes are expressed at any given time. Most of the time, the great majority of genes are silenced, locked away within a complex packaging scheme of proteins called chromatin. For a given gene to be activated when more needed, the chromatin must be opened at that location on the DNA, and that location only, to make the gene physically accessible for transcription. Histone proteins are one of the key components of chromatin structure.

Histones are relatively small proteins around which DNA coils itself to create structures called nucleosomes. Compact strings of nucleosomes, then, form into chromatin, a substructure of 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 coils of DNA around the histones are loosened, the genes become available for expression. The "histone code" theory of gene regulation, recently articulated by C. David Allis, Ph.D., at the University of Virginia, and others suggests that complex, interdependent modifications to the histones are responsible for controlling gene activity. The new data from the Wistar research team supports this idea.

The first author on the Science study is Wan-Sheng Lo, Ph.D. Wistar assistant professor Ramin Shiekhattar, Ph.D., is a co-author, and the remaining Wistar-based co-authors are Laura Duggan, Ph.D., N.C. Tolga Emre, M.S., and Rimma Belotserkovskya, Ph.D. William S. Lane at Harvard University is also a co-author.

Funding for the work was provided by the National Science Foundation and the National Institute of General Medical Sciences, one of the National Institutes of Health.

The Wistar Institute is an independent nonprofit research institution dedicated to discovering the causes and cures for major diseases, including cancer and AIDS. The Institute is a National Cancer Institute-designated Cancer Center -one of the nation's first, funded continuously since 1968, and one of only 10 focused on basic research. Founded in 1892, Wistar was the first independent institution devoted to medical research and training in the nation. Since the Institute's inception, Wistar scientists have helped to improve world health through the development of vaccines against rabies, rubella, rotavirus, and cytomegalovirus and the identification of genes associated with breast, lung, prostate and other cancers.