PU.1 positively regulates GATA-1 expression in mast cells

Clifford M Takemoto, Stephanie Brandal, Anil G. Jegga, Youl Nam Lee, Amir Shahlaee, Ye Ying, Rodney DeKoter, Michael A. McDevitt

Research output: Contribution to journalArticle

Abstract

Coexpression of PU.1 and GATA-1 is required for proper specification of the mast cell lineage; however, in the myeloid and erythroid lineages, PU.1 and GATA-1 are functionally antagonistic. In this study, we report a transcriptional network in which PU.1 positively regulates GATA-1 expression in mast cell development. We isolated a variant mRNA isoform of GATA-1 in murine mast cells that is significantly upregulated during mast cell differentiation. This isoform contains an alternatively spliced first exon (IB) that is distinct from the first exon (IE) incorporated in the major erythroid mRNA transcript. In contrast to erythroid and megakaryocyte cells, in mast cells we show that PU.1 and GATA-2 predominantly occupy potential cis-regulatory elements in the IB exon region in vivo. Using reporter assays, we identify an enhancer flanking the IB exon that is activated by PU.1. Furthermore, we observe that in PU.1 -/- fetal liver cells, low levels of the IE GATA-1 isoform is expressed, but the variant IB isoform is absent. Reintroduction of PU.1 restores variant IB isoform and upregulates total GATA-1 protein expression, which is concurrent with mast cell differentiation. Our results are consistent with a transcriptional hierarchy in which PU.1, possibly in concert with GATA-2, activates GATA-1 expression in mast cells in a pathway distinct from that seen in the erythroid and megakaryocytic lineages.

Original languageEnglish (US)
Pages (from-to)4349-4361
Number of pages13
JournalJournal of Immunology
Volume184
Issue number8
DOIs
StatePublished - Apr 15 2010

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Mast Cells
Exons
Protein Isoforms
Cell Differentiation
RNA Isoforms
Erythroid Cells
Megakaryocytes
Gene Regulatory Networks
Cell Lineage
Up-Regulation
Messenger RNA
Liver
Proteins

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

Takemoto, C. M., Brandal, S., Jegga, A. G., Lee, Y. N., Shahlaee, A., Ying, Y., ... McDevitt, M. A. (2010). PU.1 positively regulates GATA-1 expression in mast cells. Journal of Immunology, 184(8), 4349-4361. https://doi.org/10.4049/jimmunol.0900927

PU.1 positively regulates GATA-1 expression in mast cells. / Takemoto, Clifford M; Brandal, Stephanie; Jegga, Anil G.; Lee, Youl Nam; Shahlaee, Amir; Ying, Ye; DeKoter, Rodney; McDevitt, Michael A.

In: Journal of Immunology, Vol. 184, No. 8, 15.04.2010, p. 4349-4361.

Research output: Contribution to journalArticle

Takemoto, CM, Brandal, S, Jegga, AG, Lee, YN, Shahlaee, A, Ying, Y, DeKoter, R & McDevitt, MA 2010, 'PU.1 positively regulates GATA-1 expression in mast cells', Journal of Immunology, vol. 184, no. 8, pp. 4349-4361. https://doi.org/10.4049/jimmunol.0900927
Takemoto CM, Brandal S, Jegga AG, Lee YN, Shahlaee A, Ying Y et al. PU.1 positively regulates GATA-1 expression in mast cells. Journal of Immunology. 2010 Apr 15;184(8):4349-4361. https://doi.org/10.4049/jimmunol.0900927
Takemoto, Clifford M ; Brandal, Stephanie ; Jegga, Anil G. ; Lee, Youl Nam ; Shahlaee, Amir ; Ying, Ye ; DeKoter, Rodney ; McDevitt, Michael A. / PU.1 positively regulates GATA-1 expression in mast cells. In: Journal of Immunology. 2010 ; Vol. 184, No. 8. pp. 4349-4361.
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