NIH awards CSU biochemists $7.8M grant to study gene regulation within cells

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:

• Nyborg will tackle basic biochemistry that will reveal how the nucleosomes are disassembled to expose the DNA of the gene. She has developed a unique experimental system in a test-tube that resembles the process of nucleosome movement in a living cell. This system will provide a much greater understanding of nucleosome dynamics. Nyborg has been honored for her teaching and is known for her research on the human T-cell leukemia virus type 1 (HTLV-1). In recent years, HTLV-1 has become increasingly recognized as an important cause for public health concern throughout the world. Nyborg is a Professor Laureate in the College of Natural Sciences and a recipient of the Oliver P. Pennock award for Outstanding Service and the CNS Graduate Teaching and Mentoring Award.

• Luger's experiments will focus on a protein that facilitates the assembly and disassembly of the nucleosome on the DNA. She will gain an atomic level understanding of the mechanisms that cause nucleosomes to move off the DNA when genes are turned on. Luger is known for leading an extraordinary scientific breakthrough that solved the three-dimensional structure of the nucleosome in 1997. Nucleosomes, mentioned above, are small, disc-like protein-DNA structures that compact six feet of DNA into an individual cell nucleus. Luger is the first and only Howard Hughes Medical Investigator at Colorado State University in addition to being only one of a dozen University Distinguished Professors.

• Stargell, whose specialty is yeast genetics, will study the movement of nucleosomes when genes are turned on in living cells. Although her studies will be performed in yeast, the nucleosomes are evolutionarily conserved, meaning they're the same whether they're in a yeast cell or a human cell. Her work is an essential complement to the test-tube experiments conducted in the Luger and Nyborg laboratories. Stargell's research focuses on the basic mechanisms that govern genes, which is particularly important since many human diseases (including cancer) are caused by abnormal gene regulation. She recently received the CNS Graduate Education and Mentoring Award and the Jack E. Cermak Outstanding Advising Award.

"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.