A Large Gene Network in Immature Erythroid Cells Is Controlled by the Myeloid and B Cell Transcriptional Regulator PU.1

PU.1 is a hematopoietic transcription factor that is required for the development of myeloid and B cells. PU.1 is also expressed in erythroid progenitors, where it blocks erythroid differentiation by binding to and inhibiting the main erythroid promoting factor, GATA-1. However, other mechanisms by which PU.1 affects the fate of erythroid progenitors have not been thoroughly explored. Here, we used ChIP-Seq analysis for PU.1 and gene expression profiling in erythroid cells to show that PU.1 regulates an extensive network of genes that constitute major pathways for controlling growth and survival of immature erythroid cells. By analyzing fetal liver erythroid progenitors from mice with low PU.1 expression, we also show that the earliest erythroid committed cells are dramatically reduced in vivo. Furthermore, we find that PU.1 also regulates many of the same genes and pathways in other blood cells, leading us to propose that PU.1 is a multifaceted factor with overlapping, as well as distinct, functions in several hematopoietic lineages.
Author Summary Cellular identities are established by master regulatory transcription factors that promote cell type–specific gene expression. In some instances such factors also inhibit differentiation of alternative, closely related lineages. PU.1 is an Ets family transcription factor that is required for myeloid and B cell development. PU.1 is also expressed in red blood cell progenitors where it blocks erythroid terminal differentiation. One mechanism used by PU.1 to block red blood cell differentiation is by binding to and inhibiting the erythroid master regulator GATA-1. Here, we describe another mechanism utilized by PU.1 in erythroid progenitors. Using chromatin immunoprecipitation and high-throughput sequencing (ChIP-Seq) combined with gene expression profiling of erythroid progenitors, we show that PU.1 controls a large gene network in immature erythroid cells, including genes in pathways involved in regulating growth, survival, and differentiation of these cells. We also find that PU.1 controls many of the same genes and pathways in other blood cells. The results indicate that, in addition to activating lineage-specific genes, master regulatory transcription factors, like PU.1, also control numerous, widely expressed genes in multiple cell lineages.