The ETS-family transcription factor PU.1 and the GATA family transcription factor GATA1 have been shown to antagonize each other's function during haematopoiesis. Work from Walsh et al. in Immunity, shows that PU.1 can antagonize the function of GATA2 by blocking its expression, but, surprisingly, these transcription factors can also cooperate to specify mast-cell fate.

Studies with PU.1−/− mice have shown that this transcription factor is essential for the generation of myeloid and lymphoid, but not erythroid or megakaryocytic, lineages. Here, the authors establish that PU.1 is required for the survival and differentiation of mast-cell progenitors. Mast cells are absent in PU.1−/− mice, and the low number of mast-cell progenitors that are present are blocked at an early stage of development. Retroviral expression of PU.1 in PU.1−/− haematopoietic progenitors, however, allows for the development of both mast cells and macrophages.

To investigate how PU.1 regulates the mast-cell versus macrophage cell-fate decision, the authors generated a PU.1−/− progenitor cell-line that conditionally expressed an activatable form of PU.1. In this setting, active PU.1 resulted in the development of macrophages, but not mast cells. Cells that express the active form of PU.1 lacked Gata2 expression, whereas PU.1+/− and PU.1−/− cells expressed this gene, indicating that PU.1 negatively regulates the expression of Gata2.

Further experiments showed that, in the absence of Gata2, PU.1 promotes the differentiation of myeloid progenitors into macrophages — but not into mast cells — and that the re-expression of Gata2 in these progenitors resulted in the generation of mast cells. The authors propose that, during macrophage differentiation, PU.1 antagonizes Gata2 expression and function, but that PU.1 and Gata2 work together during mast-cell development.