{"gene":"MS4A2","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2014,"finding":"GATA2 directly binds the MS4A2 (FcεRIβ) promoter and transactivates it in human mast cells, as demonstrated by chromatin immunoprecipitation, luciferase reporter assay, and EMSA. PU.1 and GATA1 regulate FcεRIα but not FcεRIβ transcription. Knockdown of GATA2 reduces β-chain mRNA levels and suppresses IgE-mediated degranulation.","method":"siRNA knockdown, ChIP assay, luciferase reporter assay, EMSA, flow cytometry for surface FcεRI, degranulation assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (ChIP, EMSA, reporter assay, functional degranulation readout) in a single rigorous study","pmids":["24639354"],"is_preprint":false},{"year":2019,"finding":"In mouse mast cells, GATA2 and PU.1 cooperatively but through distinct mechanisms activate Ms4a2 (FcεRIβ) gene expression. GATA2 binds the proximal -60-bp promoter region exclusively in mast cells, while both GATA2 and PU.1 share binding to a +10.4-kbp downstream enhancer region together with the chromatin looping factor LDB1. PU.1 ablation reduces GATA2 binding at both regions. Genome editing deletion of the +10.4-kbp region completely abolishes Ms4a2 expression and FcεRI cell-surface expression.","method":"ChIP assay, genome editing (CRISPR deletion of +10.4-kbp region), siRNA knockdown, gene expression analysis, flow cytometry","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — genome editing with direct functional readout (FcεRI surface loss), combined with ChIP and epistasis experiments","pmids":["31501274"],"is_preprint":false},{"year":2006,"finding":"The MS4A2 promoter -109T allele drives higher promoter activity than the -109C allele, as demonstrated by luciferase reporter assays in RBL-2H3 and A549 cell lines, suggesting this polymorphism regulates MS4A2 transcription level.","method":"Luciferase reporter assay in mast cell and epithelial cell lines","journal":"Clinical and experimental allergy","confidence":"Medium","confidence_rationale":"Tier 2 — direct promoter activity assay with two cell lines, single lab, single method type","pmids":["16839402"],"is_preprint":false},{"year":2009,"finding":"The -109T allele of the MS4A2 promoter is associated with reduced FcεRIβ transcript levels in peripheral blood, and haplotype analysis identified promoter polymorphisms (-752C/T, -109T/C) as modulators of FcεRIβ expression, suggesting a promoter-dependent transcriptional regulatory mechanism for MS4A2.","method":"Quantitative RT-PCR for FcεRIβ mRNA, haplotype analysis in human subjects","journal":"International archives of allergy and immunology","confidence":"Low","confidence_rationale":"Tier 3 — expression measurement correlated with genotype in human subjects, no direct functional manipulation","pmids":["19218813"],"is_preprint":false},{"year":2012,"finding":"The NI-1 canine mastocytoma cell line expresses a functional IgE receptor (FcεRI, encoded in part by MS4A2/FcεRIβ) that mediates IgE-dependent mast cell activation, and NI-1 cells bearing Kit mutations show differential sensitivity to tyrosine kinase inhibitors versus mTOR/PI3K inhibitors.","method":"Cell line establishment, receptor expression characterization, functional IgE-dependent activation assay, drug sensitivity assay","journal":"Allergy","confidence":"Medium","confidence_rationale":"Tier 2 — functional IgE receptor activity demonstrated in a defined cell model with drug sensitivity profiling","pmids":["22583069"],"is_preprint":false}],"current_model":"MS4A2 (FcεRIβ), the β-chain of the high-affinity IgE receptor on mast cells and basophils, is transcriptionally activated by GATA2 via direct binding to its proximal promoter and a distal +10.4-kbp enhancer element (together with PU.1 and LDB1); loss of this enhancer abolishes FcεRI surface expression and IgE-mediated degranulation, while a common -109T/C promoter polymorphism modulates transcriptional output and downstream IgE-mediated inflammatory signaling."},"narrative":{"teleology":[{"year":2006,"claim":"Establishing that cis-regulatory variation directly modulates MS4A2 transcription: the −109T/C promoter polymorphism was shown to alter promoter activity, providing the first direct evidence that MS4A2 expression is controlled at the transcriptional level by specific promoter elements.","evidence":"Luciferase reporter assays comparing −109T and −109C allele constructs in RBL-2H3 mast cells and A549 epithelial cells","pmids":["16839402"],"confidence":"Medium","gaps":["Reporter assay in cell lines; endogenous chromatin context not tested","Transcription factor(s) differentially binding the −109 site not identified","Functional consequence on FcεRI surface expression or degranulation not measured"]},{"year":2009,"claim":"Corroborating the functional relevance of promoter polymorphisms in vivo: haplotype analysis in human subjects linked the −109T allele and −752C/T variant to differences in FcεRIβ transcript abundance in peripheral blood, connecting promoter variation to endogenous gene expression.","evidence":"Quantitative RT-PCR of FcεRIβ mRNA correlated with genotype/haplotype in human peripheral blood samples","pmids":["19218813"],"confidence":"Low","gaps":["Correlative genotype–expression association without direct functional manipulation","Cell-type-specific contribution (mast cells vs. basophils vs. other leukocytes) not resolved","No causal editing of the polymorphic site performed"]},{"year":2014,"claim":"Identifying GATA2 as the master transcriptional activator of MS4A2 in human mast cells: GATA2 was shown to directly bind the MS4A2 promoter and transactivate it, and its knockdown reduced β-chain mRNA and suppressed IgE-mediated degranulation, linking transcription factor identity to receptor function.","evidence":"ChIP, EMSA, luciferase reporter assays, siRNA knockdown of GATA2 with flow cytometry for FcεRI surface expression and degranulation assay in human mast cells","pmids":["24639354"],"confidence":"High","gaps":["Enhancer elements beyond the proximal promoter not yet mapped","Cofactors cooperating with GATA2 at the MS4A2 locus not defined","Mechanism by which β-chain loss impairs degranulation (assembly vs. signaling) not dissected"]},{"year":2019,"claim":"Defining the full cis-regulatory architecture of MS4A2: a +10.4-kbp enhancer was identified where GATA2 and PU.1 co-bind with the looping factor LDB1, and its CRISPR deletion completely abolished MS4A2 expression and FcεRI surface display, establishing that both proximal promoter and distal enhancer are required.","evidence":"ChIP for GATA2/PU.1/LDB1, CRISPR deletion of +10.4-kbp enhancer region, flow cytometry, and gene expression analysis in mouse bone-marrow-derived mast cells","pmids":["31501274"],"confidence":"High","gaps":["Physical chromatin looping between the enhancer and promoter not directly demonstrated (e.g., 3C/Hi-C)","Whether LDB1 is required or merely present at the enhancer not tested by loss-of-function","Relevance of the +10.4-kbp enhancer in human mast cells not confirmed"]},{"year":null,"claim":"It remains unknown how FcεRIβ (MS4A2) mechanistically amplifies FcεRI signaling at the molecular level, whether additional distal regulatory elements control MS4A2 in basophils versus mast cells, and how the −109T/C polymorphism intersects with GATA2-dependent activation in the native chromatin context.","evidence":"","pmids":[],"confidence":"Low","gaps":["Structural basis by which β-chain four-transmembrane topology enhances receptor complex signaling is unresolved","Basophil-specific transcriptional regulation of MS4A2 is largely uncharacterized","No integrative model combining promoter polymorphisms with GATA2/PU.1/LDB1 enhancer regulation in human cells"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,4]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,4]}],"complexes":["FcεRI (high-affinity IgE receptor)"],"partners":["GATA2","SPI1"],"other_free_text":[]},"mechanistic_narrative":"MS4A2 encodes the β-chain of the high-affinity IgE receptor (FcεRI) on mast cells and basophils, where it is essential for receptor surface expression and IgE-mediated degranulation. Transcription of MS4A2 is directly activated by GATA2, which binds the proximal promoter (~−60 bp) and cooperates with PU.1 and the chromatin looping factor LDB1 at a +10.4-kbp downstream enhancer; CRISPR deletion of this enhancer completely abolishes MS4A2 expression and FcεRI surface display [PMID:24639354, PMID:31501274]. A common −109T/C promoter polymorphism modulates MS4A2 transcriptional output, with the −109T allele driving higher promoter activity in reporter assays [PMID:16839402]."},"prefetch_data":{"uniprot":{"accession":"Q01362","full_name":"High affinity immunoglobulin epsilon receptor subunit beta","aliases":["Fc epsilon receptor I beta-chain","IgE Fc receptor subunit beta","Membrane-spanning 4-domains subfamily A member 2"],"length_aa":244,"mass_kda":26.5,"function":"High affinity receptor that binds to the Fc region of immunoglobulins epsilon. Aggregation of FCER1 by multivalent antigens is required for the full mast cell response, including the release of preformed mediators (such as histamine) by degranulation and de novo production of lipid mediators and cytokines. Also mediates the secretion of important lymphokines. Binding of allergen to receptor-bound IgE leads to cell activation and the release of mediators responsible for the manifestations of allergy","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q01362/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MS4A2","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MS4A2","total_profiled":1310},"omim":[{"mim_id":"609632","title":"GLYCEROPHOSPHODIESTER PHOSPHODIESTERASE DOMAIN-CONTAINING PROTEIN 5; GDPD5","url":"https://www.omim.org/entry/609632"},{"mim_id":"606549","title":"MEMBRANE-SPANNING 4-DOMAINS, SUBFAMILY A, MEMBER 8B; MS4A8B","url":"https://www.omim.org/entry/606549"},{"mim_id":"606548","title":"MEMBRANE-SPANNING 4-DOMAINS, SUBFAMILY A, MEMBER 6A; MS4A6A","url":"https://www.omim.org/entry/606548"},{"mim_id":"606547","title":"MEMBRANE-SPANNING 4-DOMAINS, SUBFAMILY A, MEMBER 4A; MS4A4A","url":"https://www.omim.org/entry/606547"},{"mim_id":"606502","title":"MEMBRANE-SPANNING 4-DOMAINS, SUBFAMILY A, MEMBER 7; MS4A7","url":"https://www.omim.org/entry/606502"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lung","ntpm":11.8}],"url":"https://www.proteinatlas.org/search/MS4A2"},"hgnc":{"alias_symbol":[],"prev_symbol":["FCER1B","IGER","APY"]},"alphafold":{"accession":"Q01362","domains":[{"cath_id":"-","chopping":"52-229","consensus_level":"high","plddt":86.0583,"start":52,"end":229}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01362","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q01362-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q01362-F1-predicted_aligned_error_v6.png","plddt_mean":74.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MS4A2","jax_strain_url":"https://www.jax.org/strain/search?query=MS4A2"},"sequence":{"accession":"Q01362","fasta_url":"https://rest.uniprot.org/uniprotkb/Q01362.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q01362/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01362"}},"corpus_meta":[{"pmid":"11447385","id":"PMC_11447385","title":"Increased 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PU.1 and GATA1 regulate FcεRIα but not FcεRIβ transcription. Knockdown of GATA2 reduces β-chain mRNA levels and suppresses IgE-mediated degranulation.\",\n      \"method\": \"siRNA knockdown, ChIP assay, luciferase reporter assay, EMSA, flow cytometry for surface FcεRI, degranulation assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (ChIP, EMSA, reporter assay, functional degranulation readout) in a single rigorous study\",\n      \"pmids\": [\"24639354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In mouse mast cells, GATA2 and PU.1 cooperatively but through distinct mechanisms activate Ms4a2 (FcεRIβ) gene expression. GATA2 binds the proximal -60-bp promoter region exclusively in mast cells, while both GATA2 and PU.1 share binding to a +10.4-kbp downstream enhancer region together with the chromatin looping factor LDB1. PU.1 ablation reduces GATA2 binding at both regions. Genome editing deletion of the +10.4-kbp region completely abolishes Ms4a2 expression and FcεRI cell-surface expression.\",\n      \"method\": \"ChIP assay, genome editing (CRISPR deletion of +10.4-kbp region), siRNA knockdown, gene expression analysis, flow cytometry\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genome editing with direct functional readout (FcεRI surface loss), combined with ChIP and epistasis experiments\",\n      \"pmids\": [\"31501274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The MS4A2 promoter -109T allele drives higher promoter activity than the -109C allele, as demonstrated by luciferase reporter assays in RBL-2H3 and A549 cell lines, suggesting this polymorphism regulates MS4A2 transcription level.\",\n      \"method\": \"Luciferase reporter assay in mast cell and epithelial cell lines\",\n      \"journal\": \"Clinical and experimental allergy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct promoter activity assay with two cell lines, single lab, single method type\",\n      \"pmids\": [\"16839402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The -109T allele of the MS4A2 promoter is associated with reduced FcεRIβ transcript levels in peripheral blood, and haplotype analysis identified promoter polymorphisms (-752C/T, -109T/C) as modulators of FcεRIβ expression, suggesting a promoter-dependent transcriptional regulatory mechanism for MS4A2.\",\n      \"method\": \"Quantitative RT-PCR for FcεRIβ mRNA, haplotype analysis in human subjects\",\n      \"journal\": \"International archives of allergy and immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — expression measurement correlated with genotype in human subjects, no direct functional manipulation\",\n      \"pmids\": [\"19218813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The NI-1 canine mastocytoma cell line expresses a functional IgE receptor (FcεRI, encoded in part by MS4A2/FcεRIβ) that mediates IgE-dependent mast cell activation, and NI-1 cells bearing Kit mutations show differential sensitivity to tyrosine kinase inhibitors versus mTOR/PI3K inhibitors.\",\n      \"method\": \"Cell line establishment, receptor expression characterization, functional IgE-dependent activation assay, drug sensitivity assay\",\n      \"journal\": \"Allergy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional IgE receptor activity demonstrated in a defined cell model with drug sensitivity profiling\",\n      \"pmids\": [\"22583069\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MS4A2 (FcεRIβ), the β-chain of the high-affinity IgE receptor on mast cells and basophils, is transcriptionally activated by GATA2 via direct binding to its proximal promoter and a distal +10.4-kbp enhancer element (together with PU.1 and LDB1); loss of this enhancer abolishes FcεRI surface expression and IgE-mediated degranulation, while a common -109T/C promoter polymorphism modulates transcriptional output and downstream IgE-mediated inflammatory signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MS4A2 encodes the β-chain of the high-affinity IgE receptor (FcεRI) on mast cells and basophils, where it is essential for receptor surface expression and IgE-mediated degranulation. Transcription of MS4A2 is directly activated by GATA2, which binds the proximal promoter (~−60 bp) and cooperates with PU.1 and the chromatin looping factor LDB1 at a +10.4-kbp downstream enhancer; CRISPR deletion of this enhancer completely abolishes MS4A2 expression and FcεRI surface display [PMID:24639354, PMID:31501274]. A common −109T/C promoter polymorphism modulates MS4A2 transcriptional output, with the −109T allele driving higher promoter activity in reporter assays [PMID:16839402].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Establishing that cis-regulatory variation directly modulates MS4A2 transcription: the −109T/C promoter polymorphism was shown to alter promoter activity, providing the first direct evidence that MS4A2 expression is controlled at the transcriptional level by specific promoter elements.\",\n      \"evidence\": \"Luciferase reporter assays comparing −109T and −109C allele constructs in RBL-2H3 mast cells and A549 epithelial cells\",\n      \"pmids\": [\"16839402\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Reporter assay in cell lines; endogenous chromatin context not tested\",\n        \"Transcription factor(s) differentially binding the −109 site not identified\",\n        \"Functional consequence on FcεRI surface expression or degranulation not measured\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Corroborating the functional relevance of promoter polymorphisms in vivo: haplotype analysis in human subjects linked the −109T allele and −752C/T variant to differences in FcεRIβ transcript abundance in peripheral blood, connecting promoter variation to endogenous gene expression.\",\n      \"evidence\": \"Quantitative RT-PCR of FcεRIβ mRNA correlated with genotype/haplotype in human peripheral blood samples\",\n      \"pmids\": [\"19218813\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Correlative genotype–expression association without direct functional manipulation\",\n        \"Cell-type-specific contribution (mast cells vs. basophils vs. other leukocytes) not resolved\",\n        \"No causal editing of the polymorphic site performed\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying GATA2 as the master transcriptional activator of MS4A2 in human mast cells: GATA2 was shown to directly bind the MS4A2 promoter and transactivate it, and its knockdown reduced β-chain mRNA and suppressed IgE-mediated degranulation, linking transcription factor identity to receptor function.\",\n      \"evidence\": \"ChIP, EMSA, luciferase reporter assays, siRNA knockdown of GATA2 with flow cytometry for FcεRI surface expression and degranulation assay in human mast cells\",\n      \"pmids\": [\"24639354\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Enhancer elements beyond the proximal promoter not yet mapped\",\n        \"Cofactors cooperating with GATA2 at the MS4A2 locus not defined\",\n        \"Mechanism by which β-chain loss impairs degranulation (assembly vs. signaling) not dissected\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defining the full cis-regulatory architecture of MS4A2: a +10.4-kbp enhancer was identified where GATA2 and PU.1 co-bind with the looping factor LDB1, and its CRISPR deletion completely abolished MS4A2 expression and FcεRI surface display, establishing that both proximal promoter and distal enhancer are required.\",\n      \"evidence\": \"ChIP for GATA2/PU.1/LDB1, CRISPR deletion of +10.4-kbp enhancer region, flow cytometry, and gene expression analysis in mouse bone-marrow-derived mast cells\",\n      \"pmids\": [\"31501274\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Physical chromatin looping between the enhancer and promoter not directly demonstrated (e.g., 3C/Hi-C)\",\n        \"Whether LDB1 is required or merely present at the enhancer not tested by loss-of-function\",\n        \"Relevance of the +10.4-kbp enhancer in human mast cells not confirmed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how FcεRIβ (MS4A2) mechanistically amplifies FcεRI signaling at the molecular level, whether additional distal regulatory elements control MS4A2 in basophils versus mast cells, and how the −109T/C polymorphism intersects with GATA2-dependent activation in the native chromatin context.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Structural basis by which β-chain four-transmembrane topology enhances receptor complex signaling is unresolved\",\n        \"Basophil-specific transcriptional regulation of MS4A2 is largely uncharacterized\",\n        \"No integrative model combining promoter polymorphisms with GATA2/PU.1/LDB1 enhancer regulation in human cells\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0060089\",\n        \"supporting_discovery_ids\": [4]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005886\",\n        \"supporting_discovery_ids\": [0, 1, 4]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-168256\",\n        \"supporting_discovery_ids\": [0, 1, 4]\n      }\n    ],\n    \"complexes\": [\n      \"FcεRI (high-affinity IgE receptor)\"\n    ],\n    \"partners\": [\n      \"GATA2\",\n      \"SPI1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}