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The transcription factor IRF4 regulates immunoglobulin class switch recombination and plasma cell differentiation. Its differing concentrations appear to regulate mutually antagonistic programs of B and plasma cell gene expression. We show IRF4 to be also required for generation of germinal center (GC) B cells. Its transient expression in vivo induced the expression of key GC genes including Bcl6...
Little is known about the developmental functions of chromatin regulators that can deubiquitinate histones. In this issue of Immunity, Jiang et al. (2011) demonstrate that the deubiquitinase MYSM1 is part of an epigenetic switch that turns on B cell development.
The transcription factor PU.1, encoded by the Sfpi1 gene, functions in a graded manner to regulate macrophage versus B cell generation; its higher concentration favors the macrophage fate. We demonstrated that Gfi1 reciprocally promoted B cell fate choice at the expense of myeloid progeny. Gfi1 -/- multipotential progenitors (MPPs) were unable to constrain the expression of PU.1 because Gfi1...
Productive rearrangement of the immunoglobulin heavy-chain locus triggers a major developmental checkpoint that promotes limited clonal expansion of pre-B cells, thereby culminating in cell-cycle arrest and rearrangement of light-chain loci. By using Irf4 −/− Irf8 −/− pre-B cells, we demonstrated that two pathways converge to synergistically drive light-chain rearrangement, but not...
Molecular mechanisms underlying the coordination of isotype switching with plasma cell differentiation are poorly understood. We show that interferon regulatory factor-4 (IRF-4) regulates both processes by controlling the expression of the Aicda and Prdm1 genes, which encode AID and Blimp-1, respectively. Genome-wide analysis demonstrated that Irf4 −/− B cells failed to induce the entire Blimp-1-dependent...
In this issue of Immunity, Delogu et al. (2006) and Nera et al. (2006) find that the downregulation of Pax-5 during antigen-dependent-terminal differentiation results in a substantial loss of B cell identity and the transition to a plasma cell state.
PU.1 and GATA transcription factors appear to antagonize each other's function in the development of distinct lineages of the hematopoietic system. In contrast, we demonstrate that PU.1, like GATA-2, is essential for the generation of mast cells. PU.1-/- hematopoietic progenitors can be propagated in IL-3 and differentiate into mast cells or macrophages upon restoration of PU.1 activity. Using these...
Development of the lymphoid system is dependent on the Ets family transcription factor PU.1. We demonstrate that PU.1 -/- hematopoietic progenitors fail to express IL-7Rα transcripts. Promoter and chromatin crosslinking analyses suggest that PU.1 directly regulates transcription of the IL-7Rα gene. Retroviral transduction of IL-7Rα into PU.1 -/- progenitors restores...
Transcription factor PU.1 is required for the development of lymphoid and myeloid progenitors during fetal hematopoiesis. By generating chimeric animals using PU.1 -/- ES cells or PU.1 -/- hematopoietic progenitors, we demonstrate that PU.1 functions in an exclusively cell-autonomous manner to regulate the development of the lymphoid-myeloid system. Multipotential...
We have previously shown using gene targeting that PU.1 is essential for the development of lymphoid and myeloid lineages during fetal liver hematopolesis. We now show that PU.1 is required for the maturation of yolk sac-derived myeloid progenitors and for the differentiation of ES cells into macrophages. The role of PU.1 in regulating target genes, thought to be critical in the development of monocytes...
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