GATA2 Is a Critical Transactivator for the Human IL1RL1/ST2 Promoter in Mast Cells/Basophils

Baba, Yosuke; Maeda, Keiko; Yashiro, Takashi; Inage, Eisuke; Kasakura, Kazumi; Suzuki, Ryuyo; Niyonsaba, François; Hara, Mutsuko; Tanabe, Atsushi; Ogawa, Hideoki; Okumura, Ko; Ohtsuka, Yoshikazu; Shimizu, Toshiaki; Nishiyama, Chiharu

doi:10.1074/jbc.m112.374876

Cited by 48 publications

(51 citation statements)

References 24 publications

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“…Although GATA1 was identified as a transactivator for the mouse MS4A2 (encoding FcεRIb) promoter (7,19), cell type-specific transcripThe Journal of Immunologytion factor that regulates human MS4A2 has not been identified to date. It has also been revealed that GATA2, which is also known to regulate mast cell development in a synergistic manner with PU.1 (20), is necessary for the promoter function of c-kit (18) and ST2/ IL1RL1 (IL-33R) (14) in mast cells. In the current study, we investigated the involvement of PU.1, GATA1, and GATA2 in the expression of FcεRI using a recently established highly effective knockdown of target mRNA in mast cells to verify our previous findings.…”

Section: Resultsmentioning

confidence: 99%

“…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). However, it has also been reported that knockdown of GATA1 and GATA2 by siRNA does not affect FcεRI expression in rodent mast cells and/or a basophilic cell line (10,11).…”

Section: Discussionmentioning

confidence: 99%

“…Briefly, several studies reported that PU.1 Relative mean fluorescence intensity (MFI) (bottom) was calculated in the same way as in a previous study (14). control, control siRNA transfectant; GATA1, GATA1 siRNA transfectant; GATA2, GATA2 siRNA transfectant; None, without electroporation; PU.1, PU.1 siRNA transfectant.…”

Section: Discussionmentioning

confidence: 99%

“…Transfection of siRNA was performed, as described previously (14). Briefly, 10 (or 1) ml 20 mmol/L siRNA was introduced into 2 3 10 6 (or 2 3 10 5 ) LAD2 cells or primary mast cells with a Neon 100 ml kit (or a Neon 10 ml kit) using a Neon transfection system (Invitrogen) set at Program 16 (for LAD2) or 5 (for primary mast cells).…”

Section: Cellsmentioning

confidence: 99%

“…EMSA was performed, as described previously (14,15,17,18). Abs against GATA1, GATA2, and the control Abs were same as those used in the ChIP assay.…”

Section: Emsamentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Cellsmentioning

confidence: 99%

“…EMSA was performed, as described previously (14,15,17,18). Abs against GATA1, GATA2, and the control Abs were same as those used in the ChIP assay.…”

Section: Emsamentioning

confidence: 99%

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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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Activated mast cells synthesize and release soluble ST2‐a decoy receptor for IL‐33

et al. 2015

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Interleukin 33 (IL-33) released from damaged cells plays a central role in allergic inflammation by acting through its membrane-bound receptor, ST2 receptor (ST2L). IL-33 activity can be neutralized by the soluble spliced variant of ST2 (sST2) which has been associated with allergic inflammation but its source is not well defined. We investigated whether mast cells (MCs) are a significant source of sST2 following activation through FcεRI or ST2. We find that antigen and IL-33 induce substantial production and release of sST2 from human and mouse MCs in culture and do so synergistically when added together or in combination with stem cell factor. Moreover, increases in circulating sST2 during anaphylaxis in mice were dependent on the presence of MCs. Human MCs activated via FcεRI failed to generate IL-33 and IL-33 produced by mouse bone marrow-derived MCs was retained within the cells. Therefore, FcεRI-mediated sST2 production is independent of MC-derived IL-33 acting in an autocrine manner. These results are consistent with the conclusion that both mouse and human MCs when activated are a significant inducible source of sST2 but not IL-33 and thus have the ability to modulate the biologic impact of IL-33 produced locally by other cell types during allergic inflammation.

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MYB–GATA1 fusion promotes basophilic leukaemia: involvement of interleukin‐33 and nerve growth factor receptors

Ducassou

Prouzet‐Mauléon

Deau

et al. 2017

The Journal of Pathology

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Acute basophilic leukaemia (ABL) is a rare subtype of acute myeloblastic leukaemia. We previously described a recurrent t(X;6)(p11;q23) translocation generating an MYB-GATA1 fusion gene in male infants with ABL. To better understand its role, the chimeric MYB-GATA1 transcription factor was expressed in CD34-positive haematopoietic progenitors, which were transplanted into immunodeficient mice. Cells expressing MYB-GATA1 showed increased expression of markers of immaturity (CD34), of granulocytic lineage (CD33 and CD117), and of basophilic differentiation (CD203c and FcϵRI). UT-7 cells also showed basophilic differentiation after MYB-GATA1 transfection. A transcriptomic study identified nine genes deregulated by both MYB-GATA1 and basophilic differentiation. Induction of three of these genes (CCL23, IL1RL1, and NTRK1) was confirmed in MYB-GATA1-expressing CD34-positive cells by reverse transcription quantitative polymerase chain reaction. Interleukin (IL)-33 and nerve growth factor (NGF), the ligands of IL-1 receptor-like 1 (IL1RL1) and neurotrophic receptor tyrosine kinase 1 (NTRK1), respectively, enhanced the basophilic differentiation of MYB-GATA1-expressing UT-7 cells, thus demonstrating the importance of this pathway in the basophilic differentiation of leukaemic cells and CD34-positive primary cells. Finally, gene reporter assays confirmed that MYB and MYB-GATA1 directly activated NTRK1 and IL1RL1 transcription, leading to basophilic skewing of the blasts. MYB-GATA1 is more efficient than MYB, because of better stability. Our results highlight the role of IL-33 and NGF receptors in the basophilic differentiation of normal and leukaemic cells. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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GATA2 Is a Critical Transactivator for the Human IL1RL1/ST2 Promoter in Mast Cells/Basophils

Cited by 48 publications

References 24 publications

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

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

Activated mast cells synthesize and release soluble ST2‐a decoy receptor for IL‐33

MYB–GATA1 fusion promotes basophilic leukaemia: involvement of interleukin‐33 and nerve growth factor receptors

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