Coordination of cell cycle, metabolism, and myeloid differentiation by lineage-specific transcription factors

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A central problem in biology is to understand how cells and organisms regulate cell division in response to developmental and environmental cues. During blood cell development, quiescent hematopoietic stem cells generate rapidly proliferating progenitor cells. As progenitor cells differentiate into mature cells, they gradually slow the rate of their cell cycle clock and induce changes in gene expression. There is emerging evidence that metabolic changes during hematopoietic differentiation are an important input into the cell cycle clock. This differentiation process is under the control of cell-type-specific transcription factors. Much remains to be learned about mechanisms by which cell type specific transcription factors coordinate cell cycle arrest with differentiation. PU.1 (encoded by the Spi1 gene) is an E26-transformation specific (ETS) family transcription factor that is a concentration-dependent regulator of blood cell differentiation. Differentiation of macrophages from myeloid progenitors is accompanied by a 5-fold upregulation of PU.1 concentration that is required for differentiation. Reduced PU.1 expression caused by mutation or repression leads to increased proliferation and impaired differentiation of immature myeloid progenitor cells. Reduced PU.1 expression is associated with deregulated cell cycle in hematopoietic stem cells. The long-term goal of this research program is to determine how cell cycle, metabolic changes, and terminal differentiation of myeloid cells are coordinated by transcription factors such as PU.1. We propose to use a PU.1-inducible BN cell line system developed in our laboratory as well as in vivo self-renewing macrophage populations to determine the mechanism of coordination of cell cycle arrest, metabolic changes and differentiation by PU.1. There are four questions that will be addressed by our program goals: 1) Does PU.1 directly or indirectly control the downregulation of mRNA encoded by genes that are directly bound by PU.1? 2) How does PU.1 downregulate mRNA levels for key direct target genes? 3) Is PU.1-induced downregulation of mRNAs encoded by genes involved fatty acid metabolism in charge of cell cycle arrest, or does cell cycle arrest control fatty acid metabolism? 4) Do PU.1 levels play a role in self-renewal of resident macrophage populations? These experiments are expected to result in a detailed understanding of how PU.1 regulates myeloid differentiation and self-renewal.