Nov. 17, 2003 PHILADELPHIA -- With the sequence of the human genome largely in hand and the majority of genes now available for study, scientists have increasingly turned their attention to better understanding the process of gene regulation. How is a gene turned on? How is a gene turned off? Estimates are that only one in ten genes is active in a given cell at a given time, so these questions are biologically significant. And in many ways, health turns on the appropriate and reliable control of genes. An array of disease conditions can arise if normal gene regulation is perturbed for any reason.
In the case of gene activation, past studies have revealed that specific molecular additions to DNA-packaging proteins called histones are critical to the process. A number of histones are generally involved in the packaging of a single gene, and the picture had emerged of different enzymes adding different molecular groups to different histones to achieve a series of small changes with the collective outcome of turning the gene on. In essence, additions to histones were accumulated until the "on" state was reached.
Now, a new study by researchers at The Wistar Institute reveals the gene-activation process through these molecular modifications to be more dynamic than had been appreciated previously. Specifically, the team's experiments show that, within the process of turning a gene on, the addition of a molecule called ubiquitin is required and, at a different stage of activation, the removal of ubiquitin is also necessary. A sequence of modifications is therefore involved – including some that may be reversible, it is now clear. The picture of certain molecular groups being added to histones until the cumulative changes result in gene activation now appears inadequate to explain the process. Instead, a new view that places greater emphasis on the specific order of molecular events within the process of gene activation targeting the histones now seems more informative.
A report on the study appears in the November issue of Genes & Development.
"These findings go against the paradigms that scientists have developed for gene activation," says Shelley L. Berger, Ph.D., the Hilary Koprowski Professor in the Gene Expression and Regulation Program at The Wistar Institute and senior author on the study. "What's new and different here is the idea that there is some sort of dynamic process, a required sequence of changes to the histones packaging the DNA, involved in turning genes on. Order is vital. Gene activation is an intricate, highly orchestrated, and highly regulated series of events – as it should be for something so important to life."
The new study underscores emerging ideas that these chemical modifications to histones play an active role in controlling genes. And they do not simply alter the DNA structure to permit activation, as some scientists have thought. Instead, the addition and removal of the ubiquitin group, in this case, actively recruits crucial molecules into the gene-activation process and then releases them at specific times and locations within the gene.
"The histones and the intricate pattern and sequence of modifications that plays upon them are fundamental to this process," Berger says. "Gene activation doesn't rely only on the enzymes involved in carrying out the process of 'reading' the gene. Instead, it's regulated by the underlying DNA template, provided by the associated histones, which helps orchestrate the sequence of events that results in appropriate gene expression. Furthermore, we now know that human disease – cancers and developmental disorders, for example – can result from loss of these histone controls."
The lead author on the Genes & Development study is Karl W. Henry, Ph.D., at The Wistar Institute. Co-authors at Wistar are Anastasia Wyce, Laura J. Duggan, Ph.D., and N.C. Tolga Emre, M.S. The remaining co-authors are Wan-Sheng Lo and Lorraine Pillus at the University of California, San Diego; Cheng-Fu Kao and Mary Ann Osley at the University of Mexico Health Sciences Center; and Ali Shilatifard at the Saint Louis University School of Medicine.
The research was supported by grants from the National Institutes of Health and the National Science Foundation.
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.
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