PU.1 Positively Regulates GATA-1 Expression in Mast Cells

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

doi:10.4049/jimmunol.0900927

Cited by 14 publications

(12 citation statements)

References 49 publications

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“…2007), a co‐operative interplay between PU.1 and the GATA factors has been reported in mast cells (Henkel & Brown 1994; Walsh et al. 2002; Takemoto et al. 2010).…”

Section: Discussionmentioning

confidence: 98%

GATA transcription factors are involved in IgE‐dependent mast cell degranulation by enhancing the expression of phospholipase C‐γ1

et al. 2012

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Mast cell degranulation is a dynamic, highly organized process involving numerous signaling molecules and enzymes. Although the molecular mechanisms underlying antigen-mediated mast cell degranulation have been studied intensively, little is known about the transcriptional control of this process. Here, we show that the hematopoietic transcription factors GATA1 and GATA2 are involved in mast cell degranulation through the control of phospholipase C-c1 (PLC-c1) expression. Knockdown of GATA1 and ⁄ or GATA2 by specific siRNA significantly reduced antigen-induced degranulation and Ca 2+ mobilization in the rat basophilic leukemia cell line RBL-2H3. RT-PCR analyses showed that PLC-c1 expression was significantly decreased by this GATA factor repression. Other GATA factor targets, such as the previously reported a and b subunits of the high-affinity IgE receptor (FceRI), were unaffected. Chromatin immunoprecipitation and luciferase reporter assays demonstrated that GATA factors directly activate PLC-c1 gene transcription through a conserved GATA-binding motif that resides in the 5¢-upstream sequence. Furthermore, we show evidence that the PLC-c1 expression is regulated by GATA2 in mast cells derived from mouse bone marrow. These data indicate that PLC-c1 is a target gene of GATA factors in mast cells and provide evidence that GATA1 and GATA2 control antigen-mediated mast cell degranulation by regulating the expression of PLC-c1.

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“…2007), a co‐operative interplay between PU.1 and the GATA factors has been reported in mast cells (Henkel & Brown 1994; Walsh et al. 2002; Takemoto et al. 2010).…”

Section: Discussionmentioning

confidence: 98%

GATA transcription factors are involved in IgE‐dependent mast cell degranulation by enhancing the expression of phospholipase C‐γ1

et al. 2012

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“…In contrast, PU.1 and GATA1/GATA2 exhibit a cooperative function in mast cells, as follows: 1) PU.1 and GATA2 cooperatively induce mast cell development (20); 2) PU.1 and GATA1 synergistically transactivate cell type-specific gene regulation in mast cells (5,29); and 3) PU.1 is required for GATA1 expression in mast cells (30). In our previous studies, PU.1, GATA1, and GATA2 were identified as specific transcription factors that participate in the transcriptional regulation of certain genes expressed in mast cells, including human FCER1A (FcεRIa), mouse Ms4a2 (FcεRIb), mouse c-kit, and human ST2/ IL1RL1 (4,5,7,14,18,19).…”

Section: Discussionmentioning

confidence: 99%

Critical Roles for PU.1, GATA1, and GATA2 in the Expression of Human FcεRI on Mast Cells: PU.1 and GATA1 Transactivate FCER1A, and GATA2 Transactivates FCER1A and MS4A2

Inage

Kasakura

Yashiro

et al. 2014

The Journal of Immunology

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The high-affinity IgE receptor, FcεRI, which is composed of α-, β-, and γ-chains, plays an important role in IgE-mediated allergic responses. In the current study, involvement of the transcription factors, PU.1, GATA1, and GATA2, in the expression of FcεRI on human mast cells was investigated. Transfection of small interfering RNAs (siRNAs) against PU.1, GATA1, and GATA2 into the human mast cell line, LAD2, caused significant downregulation of cell surface expression of FcεRI. Quantification of the mRNA levels revealed that PU.1, GATA1, and GATA2 siRNAs suppressed the α transcript, whereas the amount of β mRNA was reduced in only GATA2 siRNA transfectants. In contrast, γ mRNA levels were not affected by any of the knockdowns. Chromatin immunoprecipitation assay showed that significant amounts of PU.1, GATA1, and GATA2 bind to the promoter region of FCER1A (encoding FcεRIα) and that GATA2 binds to the promoter of MS4A2 (encoding FcεRIβ). Luciferase assay and EMSA showed that GATA2 transactivates the MS4A2 promoter via direct binding. These knockdowns of transcription factors also suppressed the IgE-mediated degranulation activity of LAD2. Similarly, all three knockdowns suppressed FcεRI expression in primary mast cells, especially PU.1 siRNA and GATA2 siRNA, which target FcεRIα and FcεRIβ, respectively. From these results, we conclude that PU.1 and GATA1 are involved in FcεRIα transcription through recruitment to its promoter, whereas GATA2 positively regulates FcεRIβ transcription. Suppression of these transcription factors leads to downregulation of FcεRI expression and IgE-mediated degranulation activity. Our findings will contribute to the development of new therapeutic approaches for FcεRI-mediated allergic diseases.

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“…Gata2 is required for early mast cell development, 39 whereas Gata1 is needed for mast cell maturation 42 and, indeed, appears itself to be directly regulated by Gata2 and Pu.1. 43 The zebrafish model affords the opportunity for elucidating the transcriptional regulation of many vertebrate hematopoietic lineages in vivo, including mast cells. 9,10 We previously identified cpa5 as a unique marker of zebrafish mast cells, and we characterized both pu.1 and gata2 as key transcription factors for primitive zebrafish mast cell development.…”

Section: Notch In Zebrafish Mast Cells 3589mentioning

confidence: 99%

The zebrafish reveals dependence of the mast cell lineage on Notch signaling in vivo

Da’as

Coombs

Balci

et al. 2012

Blood

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We used the opportunities afforded by the zebrafish to determine upstream pathways regulating mast cell development in vivo and identify their cellular origin. Colocalization studies demonstrated zebrafish notch receptor expression in cells expressing carboxypeptidase A5 (cpa5), a zebrafish mast cell-specific marker. Inhibition of the Notch pathway resulted in decreased cpa5 expression in mindbomb mutants and wild-type embryos treated with the ␥-secretase inhibitor, Compound E. A series of morpholino knockdown studies specifically identified notch1b and gata2 as the critical factors regulating mast cell fate. Moreover, hsp70::GAL4;UAS::nicd1a transgenic embryos overexpressing an activated form of notch1, nicd1a, displayed increased cpa5, gata2, and pu.1 expression. This increase in cpa5 expression could be reversed and reduced below baseline levels in a dose-dependent manner using Compound E. Finally, evidence that cpa5 expression colocalizes with lmo2 in the absence of IntroductionMast cells are best known for their role in acute and chronic allergic reactions; however, they also function as a crucial component in both innate and acquired immune responses 1 as well as solid tumor and leukemia progression. 2,3 Mast cells delineate from hematopoietic stem cells (HSCs) in the bone marrow but, unlike other blood cells, enter circulation as progenitors. They only complete maturation in resident tissues, which greatly hinders accurate lineage tracing studies in traditional mammalian models. 1 We have been using the zebrafish model to study mast cell development and, specifically, the transcriptional regulation of mast cell lineage commitment. The zebrafish is a highly efficient model system for studying blood cell development. 4-6 All of the major hematopoietic cellular lineages studied to date have zebrafish counterparts, and the fundamental genetic mechanisms that control hematopoiesis are well conserved. 4,7,8 We first described a mast cell counterpart in the zebrafish 9 and subsequently showed conserved roles of these cells in adaptive and innate responses to inflammatory stimuli. 10 Zebrafish carboxypeptidase a5 (cpa5) was identified as a zebrafish mast cell-specific marker, and gata2 and pu.1 were found to be the key transcription factors required for early mast cell lineage commitment in keeping with studies in mammalian systems. 9,11,12 The Notch signaling pathway is a critical regulator of cell fate determination conserved through evolution. Aberrant Notch signaling is associated with a wide range of human disorders from developmental syndromes to cancer. 13 Notch signaling is involved in the fate determination of a variety of cell types, including hematopoietic cells where it participates in differentiation, proliferation, and apoptosis. 14 In mammals, the Notch pathway consists of 4 Notch genes (Notch1-4), which encode transmembrane receptor proteins. These receptors are activated by 5 ligands encoded by the Delta and Serrate/Jagged gene families: Delta-like1, (Dll1), Dll3, Dll4, Jagged 1 (Jag1), and Jag2...

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PU.1 Positively Regulates GATA-1 Expression in Mast Cells

Abstract: Material

Cited by 14 publications

References 49 publications

GATA transcription factors are involved in IgE‐dependent mast cell degranulation by enhancing the expression of phospholipase C‐γ1

GATA transcription factors are involved in IgE‐dependent mast cell degranulation by enhancing the expression of phospholipase C‐γ1

Critical Roles for PU.1, GATA1, and GATA2 in the Expression of Human FcεRI on Mast Cells: PU.1 and GATA1 Transactivate FCER1A, and GATA2 Transactivates FCER1A and MS4A2

The zebrafish reveals dependence of the mast cell lineage on Notch signaling in vivo

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