Researchers receive $7.8 million to examine how chromosomes unravel to let genes do their jobs

Top biochemists at Colorado State University have received a $7.8 million, five-year grant from the National Institutes of Health to investigate how chromosomes untangle to expose genes that dictate cell behavior — a project that could have a significant impact on understanding human health.

Jennifer Nyborg, Karolin Luger, and Laurie Stargell, CSU professors of biochemistry and molecular biology, will study how nucleosomes — the basic unit that tightly packages DNA into chromosomes — unfolds and disassembles to expose genes that give cells their biological traits.

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, says Peter Preusch, who oversees biophysics grants at NIH's National Institute of General Medical Sciences. "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," Preusch says.

In every living cell, bulky proteins must maneuver through the densely packed nucleosomes to access the genes so DNA can be copied, first into RNA and then into protein. That process occurs with thousands of genes in every cell in the body and gives each cell its unique instructions, such as 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.

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 — unwind from the nucleosomes to allow access for copying their instructions into proteins, with a specific biological outcome for the cell, Nyborg explains. "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 scientists will tackle three independent, yet highly interdependent, biochemistry research projects through the grant, including how the nucleosomes are disassembled to expose the DNA of the gene, how nucleosomes move off the DNA when genes are turned on, and how nucleosomes move when genes are turned on in living cells.