04:23am Friday 18 October 2019

UW Researchers Map Genetic Circuitry Controlling Red Blood Cell Production

But when the process doesn’t go according to plan, it can lead to serious health issues.

For those with anemia – a low level of red blood cells – symptoms may be as mild as general fatigue or weakness. Anemia of aging or of chronic infection, on the other hand, can be severe enough to leave a person completely bed-ridden and vulnerable to a host of other ailments.

The common drug for anemia is erythropoietin, or simply EPO, a small hormone that promotes the development of red blood cells. Having more blood provides more oxygen to the muscles and aids in recovery and endurance, which is why athletes like Lance Armstrong have used EPO in blood doping. It would make sense then that EPO be the preferred therapy for anemia. However, certain dangerous forms of anemias are often EPO-resistant or EPO-insensitive.

Scientists know the process by which red blood cells are created, but the machinery that drives it – the interaction of proteins with DNA – has some serious knowledge gaps. That’s why scientists in the University of Wisconsin-Madison Blood Research Program are lifting the veil on the genetic gears of erythropoiesis, the production of red blood cells.

UW scientists have shown that an increasingly complex matrix of proteins guide Gata-1, a “master regulator” that turns hundreds of blood production-related genes on and off. Gata-1 is a transcription factor, a protein that binds to specific DNA sequences to control the use of genetic information.

“This discovery shows that this particular factor, Gata-1, uses an ensemble of mediators that we call co-regulators, and excitingly, the exact co-regulators used depend on which gene Gata-1 needs to regulate,” said Dr. Emery Bresnick, professor of cell and regenerative biology in the UW School of Medicine and Public Health (UW SMPH). “While some genes might need three co-regulators, others might need only one. The current work provides a foundation for our continuing efforts to reveal the underlying logic of how these co-regulators are utilized.”

Most people know that the early cells that give rise to red blood cells (RBCs) are produced in bone marrow. Adult stem cells in the marrow create the precursors of what eventually become RBCs. But to leave the bone marrow and enter the blood stream, those early progenitors must go through several carefully regulated cellular divisions in rapid succession.

Many of the fundamental steps involved are still unclear: what controls how the cells mature; what controls the condensation of chromatin in the cell nucleus; what triggers a unique step of RBC development called enucleation and where the cell purges its own genetic material. All those questions are under investigation, and the genetic network holds the key.

To understand how the cell guides itself through this complex process, it’s vital to know what genes are activated and how. In 2009, Bresnick’s lab and another group at Harvard Medical School determined every gene that Gata-1 regulates. Learning exactly what helps Gata-1 do its job is the next step.

The paradigm in the field is that a transcription factor often uses the same co-regulator or co-regulators to control the majority of its regulated genes. That would mean Gata-1 uses the same co-regulators to activate and repress hundreds of different genes, a daunting task in such a rapid and intricate process.

“Gata-1 uses different combinations of co-regulators at distinct loci,” said Andrew DeVilbiss, a fourth-year graduate student in the SMPH cellular and molecular pathology doctoral program. DeVilbiss made the initial discovery in Bresnick’s lab and is lead author on the paper, published online at the Proceedings of the National Academy of Sciences. “We think the combinations are dependent on the unique chromatin environment at those locations.”

The classical function of chromatin was believed to mediate the packaging DNA into a smaller volume so it can fit in a cell (unpackaged DNA would stretch two meters in length).  More recently, it has become clear the chromatin is crucial in determining whether a gene will be active or inactive, and many constituents of chromatin are targeted by regulatory mechanisms to dynamically change the cell’s transcriptome, the genes that are expressed. Transcription factors like Gata-1 recruit enzymes that modify and remodel chromatin structures to turn genes on and off, activating or deactivating their instructional code.

“The project started in an attempt to identify chromatin remodeling and modifying enzymes that are involved in – and crucial for – establishing the transcriptome and genetic networks that are responsible for developing red blood cells,” said DeVilbiss. “We found an enzyme called SetD8 that, if you remove it, Gata-1 can’t repress all of its target genes. This is a new co-regulator for Gata-1’s transcriptional function to repress genes – but importantly at only a subset of its repressed target genes.”

While basic scientific knowledge is a worthy pursuit by itself, mapping the genetic network of important processes is critical to develop new therapies. Just as it’s better to have a mechanic who knows what should be happening when things go wrong with a car, scientists who understand what should be happening at a molecular level can develop targeted therapies for major public health issues involving blood, such as leukemias and anemias.

“EPO and EPO mimetics are major components in the arsenal of drugs to treat anemia,” said Bresnick, who is the director of the UW Blood Research Program, a newly founded program that unites a wide range of blood-related research at the UW. “That’s why it’s so important to find new regulators of the process, to get beyond this reliance on EPO. One of the implications of the type of work Andrew has done is, by identifying the mechanisms that control the process, we can then exploit the mechanisms to control blood cell production, which promises to be very exciting.”

This study was funded in part by National Institutes of Health Grant DK50107, and National Institutes of Health Grant T32GM081061 (to A.W.D.), and a UW Comprehensive Cancer Center Support Grant P30 CA014520.

University of Wisconsin School of Medicine and Public Health

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