For stem cells to become red blood cells, their DNA needs to loosen up, and scientists recently gained key insight into how that happens.
The research team, which included Dustin Schones, Ph.D., assistant professor of biology, reported its findings in the Aug. 31 issue of Genome Research. The findings shine a light on the mysterious process that transforms stem cells into the specialized cells they ultimately become.
Dustin Schones studies molecules that affect the structure of DNA. (Photo by Darrin S. Joy)
Hematopoietic stem cells are the parent cells of the blood and immune system. Before they can develop into cells such as white blood cells and red blood cells, they must first activate key genes. Those genes often are wound tightly around proteins to form knots called nucleosomes, which usually bundle close together to help make up chromosomes.
These knots keep genes hidden away. For a cell to activate a gene, it often must slide the nucleosome knots away from one another, opening up the DNA so it can be read. Proteins called transcription factors then can gain access to the DNA, where they bind to areas near the gene called enhancers.
Scientists are increasingly scrutinizing these enhancers for their role in regulating genes.
Any given transcription factor generally has a matching enhancer region on DNA. When transcription factors find their matching enhancers, they bind to the enhancer and set off a sort of genetic domino effect. Gene-reading machinery kicks in, deciphering important pieces of DNA.
Schones and his colleagues wanted to understand how this transcription factor-enhancer relationship allows stem cells to mature. To do that, they looked at hematopoietic stem cells that were primed to become red blood cells.
Their findings pointed to a protein called BRG1 and how it interacts with a transcription factor called GATA1.
Previous research showed that BRG1 is somehow involved in the development of stem cells into various types of mature cells, including red blood cells, but no one was sure how. BRG1 also is a critical piece of a large conglomerate of proteins that scientists have shown helps slide nucleosomes away from each other to reveal enhancer DNA.
Schones and his colleagues tracked where BRG1 goes on chromosomes to determine its exact role. They found it homes in on GATA1 enhancers and then slides apart nearby nucleosomes.
Then they noticed something unexpected: A second transcription factor, called TAL1, moved in and bound to the DNA.
This led the researchers to believe that BRG1 and the GATA1 and TAL1 transcription factors were somehow working in concert.
“Our results suggest a series of events,” said Schones, who performed the bulk of his work on the study prior to joining City of Hope in October 2010. “GATA1 first manages to bind to its enhancer, and then it pulls in BRG1, which then slides the nucleosomes apart.” TAL1 then can bind to DNA in the area and help activate genes that lead stem cells to become red blood cells.
The result is especially interesting because it suggests a novel role for the GATA1 transcription factor, according to Schones.
“The most surprising finding was that even though GATA1 and TAL1 bind in a complex together, only TAL1 needs BRG1 to help it bind,” he said. “This suggests that GATA1 might be acting as a ‘pioneer’ factor that can bind to DNA despite the obstruction of nucleosomes.”
The scientists’ findings one day may allow researchers to guide stem cell development, leading to new therapies.
The study team also included researchers at the National Institutes of Health in Bethesda, Md., and the University of Florida College of Medicine, Gainesville, Fla.