FORT COLLINS, Colo.—With a $7.8 million, five-yeargrant from NIH's National Institute of General Medical Sciences (NIGMS) intheir pockets to help out, a team of biochemists at Colorado State University (CSU)will investigate more fully how chromosomes allow genes to do their jobs.
Under the leadership of professors JenniferNyborg, Karolin Luger and Laurie Stargell, the university will study how thebasic unit that tightly packages DNA into chromosomes, known as a nucleosome,unfolds and disassembles to expose genes that give cells their biologicaltraits.
"Because the nucleosome plays a pivotal role ingene expression, finding ways to manipulate its assembly and disassembly are ofgreat biological and potentially therapeutic interest," says Peter Preusch, whooversees biophysics grants at NIGMS. "With their strong scientificconnections—both between each other and their subprojects—Dr. Nyborg and hercolleagues are uniquely positioned to detail the mechanisms of theseprocesses."
"The question that we're asking is veryfundamental to life, and the environment here at CSU, and in the Department ofBiochemistry and Molecular Biology, gives us a significant edge," Nyborg said.
In every living cell, bulky proteins must maneuverthrough the densely packed nucleosomes to access the genes so that the DNA canbe copied—first into RNA and then into protein. That process occurs atthousands of genes in every cell in the body and results in giving each cellits unique instructions—for example, telling a liver cell how to be a livercell and not a brain cell.
But scientists have limited understanding of howthe cell gains access to individual genes that are tightly compacted intochromosomes, the team at CSU notes.
"We know that nucleosomes serve to compact the DNAto fit into a cell nucleus; what remains a long-standing mystery is how genes—encodedby the DNA—are unwound from the nucleosomes to allow access for copying theirinstructions into proteins, with a specific biological outcome for the cell,"Nyborg said. "The cell faces an enormous paradox—it must tightly wrap the DNAaround nucleosomes for compaction, but at the same time it must unwrap the DNAat specific sites to turn a gene on."
The key to this process is manipulating thenucleosomes. The cell must strategically move or remove nucleosomes from theDNA to gain access to the underlying gene.
To understand more about how genes function intheir densely packed intracellular environment, the three women will tacklethree separate but highly interdependent biochemistry research projects throughthe grant:
Nyborg will tackle basic biochemistry that willreveal how the nucleosomes are disassembled to expose the DNA of the gene. Shehas developed a unique experimental system in a test-tube that resembles theprocess of nucleosome movement in a living cell. This system will provide amuch greater understanding of nucleosome dynamics.
Luger's experiments will focus on a protein thatfacilitates the assembly and disassembly of the nucleosome on the DNA. She willgain an atomic level understanding of the mechanisms that cause nucleosomes tomove off the DNA when genes are turned on.
Stargell, whose specialty is yeast genetics,will study the movement of nucleosomes when genes are turned on in livingcells. Although her studies will be performed in yeast, the nucleosomes areevolutionarily conserved, meaning they're the same whether they're in a yeastcell or a human cell. Her work is an essential complement to the test-tubeexperiments conducted in the Luger and Nyborg laboratories. Stargell's researchfocuses on the basic mechanisms that govern genes, which is particularlyimportant since many human diseases (including cancer) are caused by abnormalgene regulation.