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HAEMATOPOIESIS: PU.1 pinned down

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Ets family member PU.1 acts, in part, by regulating the expression of the interleukin IL-7 receptor-a (IL-7ra) gene.

Gene-targeting studies have shown an important role for several transcription factors in haematopoiesis. For example, mice that are deficient for the Ets family member PU.1 exhibit a profound defect in the generation of B, T and myeloid progenitors. Previously, PU.1 has been shown to regulate the proliferation of myeloid progenitors by controlling the expression of myeloid cytokine receptor genes, including those encoding for macrophage colony-stimulating-factor (M–CSF) receptor and granulocyte CSF receptor. Although PU.1 is known to be required for early lymphoid differentiation, how it actually regulates these developmental processes is unknown. DeKoter and colleagues now report in Immunity that PU.1 acts, in part, by regulating the expression of the interleukin IL-7 receptor- alpha (IL-7r) gene; signalling downstream of this receptor is necessary for the survival and proliferation of lymphoid progenitors.

To investigate the haematopoietic developmental block in PU.1-deficient mice, the authors carried out reverse transcriptase polymerase chain reaction (RT-PCR) analysis of multipotential progenitors from the fetal livers of these mice. Of the cytokine receptor genes that were analysed, Flt3 and the common gamma (c) chain of the IL-7R were present, but the PU.1-deficient cells lacked IL-7r transcripts.

Does PU.1 directly regulate transcription of the IL-7r gene? Analysis of the IL-7r gene promoter revealed the presence of two putative PU.1 binding sites. Using gel-shift and chromatin-immunoprecipitation analysis, DeKoter and colleagues showed that one of these sites binds to PU.1 with a high affinity and that, in pro-B cells, this site is occupied by PU.1. The authors conclude that these results, together with the fact that PU.1-deficient progenitors lack IL-7r transcripts, indicate that PU.1 directly controls transcription of the IL-7r gene.

Next, retroviral transduction experiments were carried out to see if restoration of IL-7r expression in PU.1^-/- progenitors would rescue the IL-7-dependent proliferation of these cells. Transduction with IL-7r cDNA restored the ability of PU.1^-/- progenitors to proliferate in response to IL-7, and induced the generation of low numbers of CD19⁺ pro-B cells. In addition, the authors showed that transduction with Spi-B — a closely related Ets-family transcription factor — also promoted proliferation and differentiation of PU.1^-/- progenitors into pro-B cells and macrophages, but was not required for IL-7R-dependent differentiation of PU.1^-/- progenitors into pro-B cells.

The authors conclude that a significant role for PU.1 in haematopoiesis is to control the expression of myeloid and lymphoid cytokine receptor genes.

Jenny Buckland

References

ORIGINAL RESEARCH PAPER
DeKoter, R. P. et al. PU.1 regulates expression of the interleukin-7 receptor in lymphoid progenitors. Immunity 16, 297–309 (2002) [ Article] | PubMed |
FURTHER READING
O'Riordan, M. & Grosschedl, R. Transcriptional regulation of early B-lymphocyte differentiation. Immunol. Rev. 175, 94–103 (2000) | Article | PubMed |