Different levels of transcription factor coax immune cell progenitors down different developmental pathways

May 25, 2000

In a May 26, 2000 Science report, researchers from the University of Chicago provide evidence for a theory that scientists have held for a long time--that varying levels of a single transcription factor can determine the fates of developing cells.

"The idea that differing concentrations of a transcription factor can control the development of different cell types from progenitors has been a commonly held view among developmental biologists," said Harinder Singh, associate professor of molecular genetics and cell biology, Howard Hughes Medical Investigator, and senior author of the paper. "Now we have convincing evidence for this mechanism in the mammalian immune system."

Transcription factors are proteins that act as on/off switches for various genetic programs. When a transcription factor binds to DNA sites in the genome, it can activate or repress genes, thereby initiating a new developmental program.

Researchers have shown that developing fruit flies use graded levels of certain transcription factors to control the generation of different embryonic cell types, but there hasn't been strong evidence for this mechanism in mammalian systems.

Now, researchers led by Singh have shown that different concentrations of a single transcription factor called PU.1 can cause blood cell progenitors to go down different developmental pathways.

In earlier studies, Singh and his colleagues established that PU.1 is required for the development of the white blood cells, which are important players in the immune system.

But they were puzzled over how a single transcription factor could regulate the production of different kinds of white blood cells, each with its own set of distinct genes.

In the new research, Singh and postdoctoral fellow Rodney DeKoter demonstrate that depending on the concentration of PU.1, blood cell progenitors develop into B lymphocytes or macrophages--two different types of white blood cells.

Macrophages provide defense against bacteria and other pathogens by ingesting and destroying them. B lymphocytes make antibodies against foreign microbes to help the body recognize and attack them.

To study the role of PU.1 in B cell and macrophage development, Singh and DeKoter introduced the PU.1 gene into PU.1 deficient blood cell progenitors using a retroviral vector. To their surprise, they found that cells that expressed high levels of the transcription factor became exclusively macrophages, while cells expressing low levels of PU.1 developed into B cells. Furthermore, high levels of PU.1 were shown to block the development of normal B cells.

Singh and DeKoter are now studying how other transcription factors interact with PU.1 to control the development of immune cells.

"Different levels of PU.1 are just one piece of the equation," says Singh.

"There are several other transcription factors that work in concert with PU.1 to regulate the differentiation of blood cell progenitors and we hope to learn more about their interplay in the future. Once we have a deeper understanding of the regulatory circuitry, it may be possible to exploit this knowledge to efficiently generate specific immune cells from progenitors for therapeutic purposes."

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