Graded regulation of gene expression by PU.1

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Blood cells are generated from immature precursor cells through a process called differentiation. Differentiation is controlled by external factors, such as cytokines, and by internal factors, such as regulated gene expression. A protein called PU.1 is located in the nucleus of immature blood cell precursors and is essential for controlling "decisions" to differentiate into either lymphocytes or macrophages. PU.1 is an example of a protein that regulates gene expression by turning genes on or off. High levels of PU.1 efficiently promote macrophage differentiation, whereas low levels of PU.1 promote lymphocyte differentiation. However, how this works at the molecular level is not understood. In this proposal, we will determine if high PU.1 levels are able to simultaneously turn on macrophage genes and shut off lymphocyte genes. If PU.1 has both of these activities it would explain why it is so efficient at programming immature blood cell precursors. This information will allow us to design strategies to generate desired blood cell types from precursor cells in the laboratory.