Transcription factor E3, a major regulator of mast cell–mediated allergic response Zohar Yagil, PhD, Tal Hadad Erlich, MSc, Yifat Ofir-Birin, MSc, Sagi.

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Transcription factor E3, a major regulator of mast cell–mediated allergic response Zohar Yagil, PhD, Tal Hadad Erlich, MSc, Yifat Ofir-Birin, MSc, Sagi Tshori, MD, PhD, Gillian Kay, PhD, Zanna Yekhtin, BSc, David E. Fisher, MD, PhD, Chang Cheng, PhD, W. S. Fred Wong, PhD, Karin Hartmann, MD, Ehud Razin, PhD, Hovav Nechushtan, MD, PhD Journal of Allergy and Clinical Immunology Volume 129, Issue 5, Pages 1357-1366.e5 (May 2012) DOI: 10.1016/j.jaci.2011.11.051 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Evaluation of mast cell numbers in WT and TFE3−/− mice. A and B, Toluidine blue (Fig 1, A) and Alcian blue (Fig 1, B) staining of lung (Fig 1, A) and skin (Fig 1, B) sections of WT and TFE3−/− mice. Mast cells are indicated with black arrows. One representative result of 7 experiments is shown. C, Flow cytometry of peritoneal mast cells. Dot plot analysis of FcεRIα and Kit staining of the peritoneal cell population of TFE3−/− and WT mice is shown. One representative result of 7 experiments is shown. D, Bar diagram of the mean percentage of cells double stained with FcεRIα and Kit in the peritoneal population derived from WT and TFE3−/− mice. Results represent means ± SEMs (n = 7, P ≤ .001). Journal of Allergy and Clinical Immunology 2012 129, 1357-1366.e5DOI: (10.1016/j.jaci.2011.11.051) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 TFE3 directly associates with the Kit promoter. ChIP of BMMC lysate from quiescent or 4-hour-activated WT and tg/tg BMMCs with TFE3 antibody is shown. The extracted DNA was quantified, equalized, and used as a template for real-time PCR with specific primers to detect the Kit promoter. Results represents means ± SEMs (n = 3, P ≤ .001). Journal of Allergy and Clinical Immunology 2012 129, 1357-1366.e5DOI: (10.1016/j.jaci.2011.11.051) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Redundant effect between TFE3 and MITF. A, Effect of mast cell activation on expression of TFE3. A marked increase in TFE3 transcript was observed in BMMCs derived from both WT and tg/tg mice (1.64 ± 0.26– and 2.26 ± 0.54–fold increase, respectively [means ± SEMs]; n = 5). B, Quantification of TFE3 transcript in nonrelevant siRNA (NR) and TFE3-specific (siTFE3) treated tg/tg BMMCs (n = 6, P ≤ .017). C, Effect of TFE3 silencing on MITF target genes in tg/tg BMMCs. Forty-eight hours after TFE3 silencing, the expression of Kit, Gzmb, Mcpt4, and Tpsb2 transcripts was monitored by means of real-time PCR. Results were normalized to ubiquitin C. Results represent means ± SEMs (n = 4, P ≤ .037). D, Effect of TFE3 silencing on MITF target genes after activation of BMMCs. Results were normalized to ubiquitin C and represent means ± SEMs (n = 4, P ≤ .05). Journal of Allergy and Clinical Immunology 2012 129, 1357-1366.e5DOI: (10.1016/j.jaci.2011.11.051) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 TFE3 directly regulates FcεRIα expression. A, Effect of TFE3 silencing on FcεRIα expression in tg/tg BMMCs. BMMCs were cultured for 28 days and then treated with nonrelevant siRNA (NR) or TFE3 siRNA for 72 hours. Results represent means ± SEMs (n = 4, P ≤ .035). B, FcεRIα transcript levels in BMMCs derived from knockout mice. Results represent means ± SEMs (n = 3, P ≤ .034). C, ChIP of BMMC lysate from WT BMMCs with TFE3 antibody. The extracted DNA was quantified and used as the template for real-time PCR with specific primers to detect FcεRIα promoter. Results represent means ± SEMs (n = 3, P ≤ .001). D, ChIP of BMMC lysate from tg/tg BMMCs with TFE3 antibody. Results represents means ± SEMs (n = 3, P ≤ .001). Ubc, Ubiquitin C. Journal of Allergy and Clinical Immunology 2012 129, 1357-1366.e5DOI: (10.1016/j.jaci.2011.11.051) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Effect of TFE3 on BMMC markers. A, Flow cytometric analysis of BMMCs derived from WT, tg/tg, and TFE3−/− mice. Cells were stained for FcεRI and Kit and analyzed by using flow cytometry. A dot plot of FcεRI- and Kit-stained cells is shown. One representative result of 5 experiments is shown. B, Effect of TFE3 silencing on WT and tg/tg BMMC numbers. Cells were double stained with FcεRI and Kit and analyzed by using ImageStream flow cytometry (n = 3, P ≤ .05). NR, Nonrelevant siRNA; Ssc, side scatter. Journal of Allergy and Clinical Immunology 2012 129, 1357-1366.e5DOI: (10.1016/j.jaci.2011.11.051) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Functional analysis of BMMCs from TFE3−/− mice. A, Degranulation assay. Cells were sensitized to IgE/DNP and analyzed for β-hexosaminidase activity (n = 3). B-E, Analysis of BMMC-secreted mediators. Twenty hours after an immunologic trigger, BMMC supernatants were subjected to ELISA for analysis of mast cell–secreted mediators. The secreted concentrations of IL-4, IL-6, Gzmb, and TNF-α were calculated as described in the Methods section. Results are shown as means ± SEMs (n = 3, P ≤ .03). Journal of Allergy and Clinical Immunology 2012 129, 1357-1366.e5DOI: (10.1016/j.jaci.2011.11.051) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 In vivo allergic response assay. Mice were sensitized with IgE anti-DNP through injection to the tail vein. Twenty-four hours later, mice were challenged with DNP-BSA for 1.5 minutes. Plasma was collected, and histamine levels were measured by using competitive ELISA. The histamine level in plasma from WT mice was 749.6 ± 76.5 ng/mL compared with 304.2 ± 78.8 ng/mL in plasma cells from TFE3−/− mice (n = 6, P ≤ .003). Journal of Allergy and Clinical Immunology 2012 129, 1357-1366.e5DOI: (10.1016/j.jaci.2011.11.051) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Phylogenetic tree of MiT family members. Protein sequences of the MiT family members were retrieved from GenBank: MITF (Q08874), TFE3 (NP_766060), TFEB (NP_035679), and TFEC (Q9WTW4). Multiple sequence alignment was performed by using the National Center for Biotechnology Information’s Constraint-based Multiple Alignment Tool (COBALT; http://www.ncbi.nlm.nih.gov/tools/cobalt/cobalt.cgi), and a phylogenetic tree was constructed by using National Center for Biotechnology Information’s Phylo TreeView. Values describe the levels of similarity and identity among 4 MiT family members. Journal of Allergy and Clinical Immunology 2012 129, 1357-1366.e5DOI: (10.1016/j.jaci.2011.11.051) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Additional FACS data. A, Dot plot of WT and TFE3−/− scatter values. One hundred thousand cells were collected with a LSRII flow cytometer. Data were analyzed by using FCS express software, as mentioned in the Methods section. The estimated location of the mast cell population based on reverse gating of Kit and FcεRIα double staining is marked by a blue circle. FSC, Forward scatter; SSC, side scatter. B, Distribution of Kit and FcεRIα double-stained cells in whole peritoneal population. Data shown are from 1 representative experiment of 7 independent biological repeats. FSC, Forward scatter; SSC, side scatter. C, Identification of mast cells as the population with low forward scatter (FSC) and high side scatter (SSC; I and III) by means of reverse gating of double-stained cells (II). D, I, Distribution of Kit and FcεRIα double-stained cells in the peritoneal population in WT and TFE3−/− mice. II, Histogram plot of FcεRIα expression in the same experiment. The gated population was defined by high side scatter and low forward scatter, as shown in Fig E2, B. Data shown are from 1 representative experiment of 7. Journal of Allergy and Clinical Immunology 2012 129, 1357-1366.e5DOI: (10.1016/j.jaci.2011.11.051) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 TFE3 directly associates with c-KIT promoter. ChIP of BMMC lysate from WT BMMCs with TFE3 antibody. The lysate of resting and 4-hour-activated cells was extracted and subjected to ChIP. The extracted DNA was quantified and used as a template for real-time PCR with specific primers to detect Kit promoter. Primers to detect ubiquitin C DNA were used as negative controls. Results represent means ± SEs (n = 3, P ≤ .05). Journal of Allergy and Clinical Immunology 2012 129, 1357-1366.e5DOI: (10.1016/j.jaci.2011.11.051) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions