Wisconsin Scientists Assemble Puzzle of Red Blood Cell Genes
MADISON - A complete picture of all genes involved in the formation of red blood cells--and the way the genes work with key proteins--is now available.
Researchers at the University of Wisconsin School of Medicine and Public Health (SMPH) have identified the 4,061 genes that interact with the two proteins (GATA-1 and GATA-2) that are essential for red blood cell development.
Focusing on one cluster of red blood cell genes associated with leukemia in mice, the researchers identified a pathway that may be important in understanding the disease in humans.
In addition to leukemia, the findings, reported in the current (Nov. 25, 2009) Molecular Cell, should have implications for understanding anemias associated with aging, infection and genetic mutations.
For red blood cells to develop, thousands of genes must work together, explains senior author Dr. Emery Bresnick, an SMPH professor of pharmacology and medicine (hematology/oncology) and an expert on GATA factors and blood.
GATA factors create the network and keep it running smoothly by turning the genes on and off at the right time.
"If something goes wrong anywhere or at any time in this genetic network, the results can be disastrous," says Bresnick, based in the Wisconsin Institutes for Medical Research and affiliated with the UW-Madison Carbone Cancer Center.
Too few red blood cells can lead to dangerous anemias affecting the elderly, cancer patients on chemotherapy and people with sickle cell anemia and thalassemia. Too many red blood cell precursors can produce certain kinds of leukemias.
From earlier studies, scientists have known some of the genes that are involved in this network, but now Bresnick and his collaborators have completed the picture using a living cell. The new collection includes genes that turn other genes on and off, signaling molecules and proteins that are the structural building blocks of red blood cells.
"It is particularly challenging to understand how the network works when important pieces of the puzzle are missing," Bresnick says. "Establishing the complete ensemble of genes that GATA factors interact with in a living human cell revealed a rich collection of targets for modulating blood cell development and function."
The scientists also showed the precise DNA sequence in each gene where GATA factors dock, information that suggests how the genes and factors work together. A total of 5,749 sites--more than one on some individual genes--were identified.
The findings are an important first step in understanding how red blood cells are formed in a highly complex and dynamic process directed by GATA factors.
"The next step is to determine how all the genes and GATA factors connect and function together," says Bresnick.
To illustrate the point, he and his team focused on one component of the gene network involving a blood-cell regulator called ETO-2. The protein has been shown to regulate blood cell development in mice and to function in a complex with other regulators of blood cell development. ETO-2's corresponding gene in humans is disrupted in a subset of acute myeloid leukemia cases.
Experiments on the ETO-2 gene and genes that encode ETO-2-interacting proteins, outlined in the second half of the paper, showed that GATA-1 and GATA-2 work together to interact at specific sites with ETO-2, and that ETO-2 controls the expression of its own gene.
"These studies provide a conceptual framework for understanding how the actions of GATA factors and ETO-2 coalesce to control the development of red blood cells and instigate leukemia," Bresnick says.
Key collaborators for this multidisciplinary study included Sunduz Keles, an SMPH expert in biostatistics and computational biology; Peggy Farnham, a genomics expert at the University of California-Davis; and Kyunghee Choi, an expert in stem cell biology at Washington University School of Medicine. Tohru Fujiwara of the SMPH, Henriette O'Geen of UC-Davis and Keles shared first authorship.
Date Published: 11/25/2009