FORT COLLINS - A team of top biochemists at Colorado State University will investigate how chromosomes untangle to expose genes that dictate cell behavior – a unique project that could have a significant impact on understanding human health.
The National Institutes of Health today announced it has awarded Professor Jennifer Nyborg, University Distinguished Professor Karolin Luger and Professor Laurie Stargell a $7.8 million, five-year grant to study how the basic unit that tightly packages DNA into chromosomes, known as a nucleosome, unfolds and disassembles to expose genes that give cells their biological traits.
"Fostering collaboration between scientists can ultimately lead to very important breakthroughs and greater understanding of how DNA works," said Tony Frank, president of Colorado State University. "Pooling our strengths in these areas creates great potential. This grant from NIH is an endorsement that Colorado State University is home to some of the top scientists addressing basic science with the potential to solve global health concerns."
"Because the nucleosome plays a pivotal role in gene expression, finding ways to manipulate its assembly and disassembly are of great biological and potentially therapeutic interest," said Peter Preusch, who oversees biophysics grants at NIH's National Institute of General Medical Sciences, which supports this new grant. "With their strong scientific connections—both between each other and their subprojects—Dr. Nyborg and her colleagues are uniquely positioned to detail the mechanisms of these processes."
Nyborg serves as the principal investigator on the NIH grant, known as a Program of Projects, which is expected to provide funding for as many as 15 post-doctoral positions, graduate students and technicians. Undergraduate students will also gain from hands-on instruction from some of the university's top researchers and teachers.
"The question that we're asking is very fundamental to life, and the environment here at CSU, and in the Department of Biochemistry and Molecular Biology, gives us a significant edge," Nyborg said.
In every living cell, bulky proteins must maneuver through the densely packed nucleosomes to access the genes so that the DNA can be copied – first into RNA and then into protein. That process occurs at thousands of genes in every cell in the body and results in giving each cell its unique instructions – for example, telling a liver cell how to be a liver cell and not a brain cell.
But scientists have limited understanding of how the cell gains access to individual genes that are tightly compacted into chromosomes.
"We know that nucleosomes serve to compact the DNA to fit into a cell nucleus; what remains a long-standing mystery is how genes - encoded by the DNA - are unwound from the nucleosomes to allow access for copying their instructions into proteins – with a specific biological outcome for the cell," Nyborg said. "The cell faces an enormous paradox – it must tightly wrap the DNA around nucleosomes for compaction, but at the same time it must unwrap the DNA at specific sites to turn a gene on."
The key to this process is manipulating the nucleosomes. The cell must strategically move or remove nucleosomes from the DNA to gain access to the underlying gene.
To understand more about how genes function in their densely packed intracellular environment, the three women will tackle three independent, yet highly interdependent biochemistry research projects through the grant:
"Each of the three projects will benefit significantly from the contributions of our co-Investigator, Dr. Jeffrey Hansen, the established expert in the field of chromatin dynamics and the function of nucleosomes in genome compaction," Luger said. "We're also grateful that the grant will support infrastructure and access to a network of other experts in this field. Colorado State University and our department have been very helpful in providing us with the resources to make this science possible."
Nyborg added that the team has been working together on related projects for nearly 10 years.
"We have a superb concentration of expertise that grew out of a prestigious W.M. Keck Foundation grant awarded to members of this group in January 2004," Nyborg said. "That grant, which Dr. Frank helped us obtain, provided the foundation for the research we're doing today."
The $1.2 million Keck grant allowed Nyborg, Luger, Paul Laybourn and Jeffrey Hansen the ability to apply cutting-edge techniques of structural biology and molecular genetics to address the basic question of how genes are regulated within a cell. Collectively, the team has developed a series of highly innovative and unique techniques that allow them to characterize the structural and biochemical properties of the nucleosome, and how they are modified to allow genes to be turned on and off.
Note to Reporters: Video and downloadable photos and audio of the scientists is available with the news release at http://www.colostate.edu/media/nih-grant.aspx .