PHILADELPHIA – In higher order animals, genetic information is passed from parents to offspring via sperm or eggs, also known as gametes. In some single-celled organisms, such as yeast, the genes can be passed to the next generation in spores. In both reproductive strategies, major physical changes occur in the genetic material after it has been duplicated and then halved on the way to the production of mature gametes or spores. Near the end of the process, the material – called chromatin, the substructure of chromosomes – becomes dramatically compacted, reduced in volume to as little as five percent of its original volume.
Researchers at The Wistar Institute, studying the mechanisms that control how the genetic material is managed during gamete production, have now identified a single molecule whose presence is required for genome compaction. Their experiments showed that the molecule "marks" the chromatin just prior to compaction and that its presence is mandatory for successful compaction. Additionally, after first noting the molecule's activity during the production of yeast spores, the scientists saw the same activity during the creation of sperm in fruit flies and mice, suggesting that the mechanisms governing genome compaction are evolutionarily ancient, highly conserved in species whose lineages diverged long ago. A report on the new study appears in the September 15 issue of Genes & Development. A "Perspectives" review in the same issue expands on the significance of the findings.
"This molecular mark is required at a critical time leading up to genome compaction in spores and sperm," says Shelley L. Berger, Ph.D., the Hilary Koprowski Professor at The Wistar Institute and senior author on the study. "Also, there seems to be a similarity in the way the mark is used in organisms as different from each other as yeast and mammals, suggesting that compaction has been important throughout evolution."
Berger speculates that compaction might answer a number of important biological purposes.
"During the time the DNA is single-stranded, as it is in the gametes, it's much more susceptible to breaks and mutations," she says. "Compaction may keep the genome resistant to damage of all kinds. This is critical – if the single-stranded DNA in gametes breaks, it can fall apart and possibly reassemble itself in devastating translocations."
She notes that normal double-stranded DNA, on the other hand, has the ability to repair breaks in one of its single strands by using the chemical bases in the companion strand as a reference. Bases in DNA pair only in predetermined combinations, so that one strand can serve as a template for the other.
"Compaction might also affect sperm fertility and function in the higher organisms, and thus the propagation of the species," says Thanuja Krishnamoorthy, Ph.D., lead author on the study. "It's vital that we better understand genome compaction during the production of mature sperm."
The molecule in question is a phosphorous molecule that modifies a histone. Histones are 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.
To test the team's observations, Krishnamoorthy performed an experiment in yeast in which she altered the histone's chemical composition at a single point, the point at which the molecule attaches to, or marks, the histone. The results were clear and compelling: With the alteration, the molecule was unable to attach to the histone, and compaction was severely limited.
"We saw a significant increase in genomic volume in the resulting yeast spores, as though the compaction had been lost," Berger says. "The frequency of successful spore creation was also lowered significantly."
With lead author Krishnamoorthy and senior author Berger, the other Wistar-based co-author on the study is Jean A. Dorsey. The additional co-authors are Xin Chen and Margaret Fuller with Stanford University School of Medicine; Jerome Govin and Saadi Khochbin with the Institut Albert Bonniot Faculté de Médecine in La Tronche, France; Wang L. Cheung and C. David Allis at the University of Virginia, Charlottesville; Karen Schindler and Edward Winter at Thomas Jefferson University; and Vincent Guacci at the Carnegie Institution, Baltimore. (Cheung is currently at the Johns Hopkins Hospital, and Allis is with the Rockefeller University.)
The "Perspectives" review of the study was authored by Kristy D. Wendt and Ali Shilatifard at the St. Louis University School of Medicine.
Support for the research was provided by the National Institutes of Health and the National Science Foundation. Additional support came from Lyon Rhône-Alpes Cancéropôle and the Regulome consortium, the Leukemia and Lymphoma Society, and the Commonwealth Universal Research Enhancement Program of the Pennsylvania Department of Health.
The Wistar Institute is an international leader in biomedical research, with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the country, Wistar has long held the prestigious Cancer Center designation from the National Cancer Institute. Discoveries at Wistar have led to the creation of the rubella vaccine that eradicated the disease in the U.S., rabies vaccines used worldwide, and a new rotavirus vaccine approved in 2006. Wistar scientists have also identified many cancer genes and developed monoclonal antibodies and other important research tools. Today, Wistar is home to eminent melanoma researchers and pioneering scientists working on experimental vaccines against flu, HIV, and other diseases. The Institute works actively to transfer its inventions to the commercial sector to ensure that research advances move from the laboratory to the clinic as quickly as possible. The Wistar Institute: Today's Discoveries – Tomorrow's Cures. On the web at www.wistar.org.
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