"This showed for the first time how this mixed lineage pattern is set up," Singh said.
When they increased the concentration of PU.1, however, the cells quickly passed through a transitory mixed lineage state and produced new regulatory proteins that activated macrophage genes and repressed neutrophil genes. Higher levels of C/EBP tipped the balance the other way.
The researchers were then able to identify both sets of antagonistic secondary regulators. Egr-1 and Egr-2 activate macrophage and repress neutrophil genes. Gif-1 is required to turn on neutrophil genes and repress macrophage counterparts.
Such counteracting repression circuitry may be the key to understanding stem cell regulation in general, Singh said. "We think that if this property of mixed lineage transcriptional priming is shared amongst different kinds of stem cells, then resolving these mixed-lineage states will invariably involve counteracting repressors."
In collaboration with colleague Aaron Dinner, the research team also formulated a mathematical model that depicts the regulatory network governing progenitor cell development. This model, he said, could have important implications for the therapeutic use of stem cells to rejuvenate damaged tissues.
Understanding of leukemias also could be aided by insight into this regulatory circuitry, Singh said. Many leukemias exhibit mixed-lineage patterns of gene expression, for example of both macrophage and lymphocyte genes.
"It may be that these cells are stuck in a progenitor-like state," said Singh. "If you could induce them to resolve that state X to differentiate into one or the other cell type X they would cease to be tumorigenic."
'"/>
Contact: John Easton
john.easton@uchospitals.edu
773-702-6241
University of Chicago Medical Center
30-Aug-2006