{"gene":"IRF2BP2","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2010,"finding":"IRF2BP2 was identified as a novel component of the TEAD4/VGLL4 transcription factor complex via yeast 2-hybrid screen from a human heart cDNA library, confirmed by coimmunoprecipitation and mammalian 2-hybrid assays. Coexpression of IRF2BP2 with TEAD4/VGLL4 or TEAD1 potently activated VEGFA expression, while knockdown of IRF2BP2 reduced VEGFA expression in C2C12 muscle cells.","method":"Yeast 2-hybrid, coimmunoprecipitation, mammalian 2-hybrid, siRNA knockdown","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP and functional KD with defined gene expression readout, moderate evidence","pmids":["20702774"],"is_preprint":false},{"year":2008,"finding":"IRF2BP2 was identified as a direct transcriptional target of p53. Upregulation of IRF2BP2 after actinomycin D treatment is p53-dependent. Overexpressed IRF2BP2 impedes p53-mediated transactivation of p21 and Bax genes. Knockdown of IRF2BP2 leads to upregulation of p21 and faster induction of apoptosis after doxorubicin or actinomycin D treatment, indicating IRF2BP2 modulates cell survival decisions during p53 stress response.","method":"Luciferase reporter assay, siRNA knockdown, overexpression in multiple cell lines, actinomycin D/doxorubicin treatment","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (reporter, KD, OE) with defined phenotypic readout in multiple cell lines","pmids":["19042971"],"is_preprint":false},{"year":2015,"finding":"IRF2BP2 is required for MEF2-dependent activation of KLF2 (Krüppel-like factor 2) in macrophages. Promoter studies revealed this dependence. IRF2BP2-deficient macrophages have markedly reduced KLF2 expression, impaired cholesterol efflux due to inability to activate ABCA1, and increased M1 inflammatory activation. Restoring KLF2 in IRF2BP2-deficient macrophages rescued these defects.","method":"Macrophage-specific conditional knockout mice, promoter/luciferase assay, cholesterol efflux assay, genetic rescue experiment","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with multiple orthogonal functional readouts and rescue experiment, replicated in vivo","pmids":["26195219"],"is_preprint":false},{"year":2016,"finding":"Ectopic expression of IRF2BP2 in murine primary CD4 T cells reduced CD25 expression, STAT5 phosphorylation, CD69 expression, and impaired proliferative capacity. In vivo, IRF2BP2-overexpressing transferred cells displayed impaired expansion, establishing IRF2BP2 as a repressor of naive CD4 T cell activation and clonal expansion downstream of TCR triggering.","method":"Retroviral transduction of primary murine CD4 T cells, in vivo adoptive transfer, flow cytometry, phospho-STAT5 analysis","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 — clean OE with defined cellular phenotype in vitro and in vivo, single lab","pmids":["27286791"],"is_preprint":false},{"year":2017,"finding":"IRF2BP2 directly interacted with the C-terminal transactivation domain of NFAT1, competing with MEF2C and disturbing their transcriptional synergism, thereby inhibiting NFAT1-transactivated hypertrophic transcriptome. Cardiomyocyte-specific Irf2bp2 knockout exacerbated aortic banding- and angiotensin II-induced cardiac hypertrophy, while Irf2bp2 transgenic overexpression was protective. The effect of Irf2bp2 deficiency was rescued by NFAT1 blockade.","method":"Cardiomyocyte-specific conditional KO and transgenic overexpression mice, Co-IP, epistasis rescue by NFAT1 blockade, aortic banding/angiotensin II models","journal":"Hypertension","confidence":"High","confidence_rationale":"Tier 2 — genetic KO, transgenic OE, direct protein interaction, epistasis rescue; multiple orthogonal methods","pmids":["28716987"],"is_preprint":false},{"year":2017,"finding":"Loss of IRF2BP2 in microglia leads to increased inflammatory cytokine expression in response to LPS and impaired anti-inflammatory marker activation in response to IL-4. IRF2BP2-deficient mice had larger brain infarctions after photothrombotic stroke with fewer anti-inflammatory M2 microglia. IRF2BP2 also mediates the anti-inflammatory and neuroprotective effect of IFNβ, which was lost in IRF2BP2-deficient macrophages.","method":"Macrophage/microglia-specific conditional KO mice, photothrombosis stroke model, LPS/IL-4 stimulation, cytokine measurement, IFNβ treatment","journal":"Frontiers in cellular neuroscience","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with defined in vivo and in vitro phenotypic readouts, epistasis with IFNβ","pmids":["28769762"],"is_preprint":false},{"year":2019,"finding":"IRF2BP2 overexpression suppresses osteoclast differentiation and enhances osteoblast differentiation; these effects were reversed by KLF2 knockdown, establishing the IRF2BP2/KLF2 axis as a regulator of osteoclast and osteoblast differentiation.","method":"Overexpression and siRNA knockdown in osteoclast precursor cells and osteoblasts, differentiation assays, marker gene expression","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis with KLF2 rescue, single lab","pmids":["31186082"],"is_preprint":false},{"year":2019,"finding":"IRF2BP2 modulates glucocorticoid receptor (GR) and NF-κB transcriptional activity. GC treatment changes chromatin binding of IRF2BP2, with IRF2BP2-binding sites co-occurring with GR binding sites. Depletion of IRF2BP2 modulates transcription of GC-regulated genes and alters responses to both glucocorticoids and TNF in A549 cells, positioning IRF2BP2 as a coregulator of GR-NF-κB crosstalk.","method":"ChIP-seq, siRNA knockdown, transcriptomic analysis in HEK293 and A549 cells","journal":"Journal of steroid biochemistry and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP-seq + KD with transcriptomic readout, single lab, moderate evidence","pmids":["31145973"],"is_preprint":false},{"year":2019,"finding":"In zebrafish, VGLL4 sequesters IRF2BP2 via the VGLL4 TDU1 and IRF2BP2 RING finger domains, thereby inhibiting IRF2BP2's repression of alas2 (aminolevulinate synthase 2) expression and heme biosynthesis. IRF2BP2 depletion rescued impaired erythroid terminal differentiation in vgll4b-deficient zebrafish, establishing an oxygen-sensing pathway: NOTCH1→HIF1α→VGLL4→IRF2BP2→alas2.","method":"CRISPR/Cas9 knockout zebrafish, genetic epistasis rescue (irf2bp2 depletion rescuing vgll4b mutant), domain-mapping experiments","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 2 — CRISPR KO with epistasis rescue, domain-level mechanism, ortholog (zebrafish)","pmids":["31539803"],"is_preprint":false},{"year":2020,"finding":"IRF2BP2 directly binds the promoter region of ATF3 (activating transcription factor 3) as a transcriptional repressor, as demonstrated by ChIP-seq and luciferase assay. Hepatocyte-specific Irf2bp2 knockout exacerbated high-fat diet-induced hepatic steatosis, while Irf2bp2 overexpression was protective. ATF3 knockdown significantly relieved IRF2BP2 knockout-exaggerated hepatosteatosis in vitro.","method":"Hepatocyte-specific conditional KO and adeno-associated virus overexpression in mice, ChIP-seq, luciferase assay, digital gene expression, ATF3 siRNA rescue","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 1/2 — ChIP-seq + luciferase + genetic epistasis rescue, multiple orthogonal methods","pmids":["31529495"],"is_preprint":false},{"year":2020,"finding":"miR-155-5p targets IRF2BP2 mRNA (validated by luciferase reporter assay). Immunoprecipitation showed that IRF2BP2 binds NFAT1, and oroxylin A increases this binding, reducing iNOS-driven inflammation. shRNA knockdown of miR-155-5p in bone marrow ameliorated LPS-induced acute lung injury in mice.","method":"Luciferase reporter assay, immunoprecipitation, shRNA in vivo, LPS-induced lung injury mouse model","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP and reporter assay showing IRF2BP2-NFAT1 interaction, single lab","pmids":["33052070"],"is_preprint":false},{"year":2021,"finding":"IRF2BP2 is required to attenuate STAT1 transcriptional activity; IRF2BP2 c.625_665del mutation failed to suppress STAT1 transcriptional activity in a luciferase reporter system. Patient cells with this mutation showed overexpression of STAT1 protein and increased constitutive activation of STAT1 and STAT5, as well as elevated interferon-inducible gene expression.","method":"Luciferase reporter system, flow cytometry (phospho-STAT), patient PBMC analysis, NanoString gene expression","journal":"Pharmaceuticals","confidence":"Medium","confidence_rationale":"Tier 2/3 — reporter assay + patient cell analysis; single lab, moderate evidence","pmids":["34451894"],"is_preprint":false},{"year":2022,"finding":"IRF2BP2 was identified as a novel HNF4α co-repressor. This interaction could not be detected by conventional immunoprecipitation but was identified through novel proteomic techniques sensitive to biochemically labile interactions. IRF2BP2 repressed HNF4α transcriptional activity dependent on its E3 ubiquitin ligase activity. IRF2BP2 deficiency in HepG2 cells induced gluconeogenic genes comparable to forskolin-treated wild-type cells.","method":"Novel proteomic approach for biochemically labile interactions, luciferase reporter assay, IRF2BP2 gene deletion in HepG2 cells, E3 ubiquitin ligase domain mutant","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1/2 — novel proteomic identification, reporter assay, mutant analysis; single lab","pmids":["35609419"],"is_preprint":false},{"year":2023,"finding":"Agmatine binds directly to IRF2BP2 (identified by protein microarray). This competitive binding frees IRF2BP2-bound IRF2, allowing free IRF2 to translocate to the nucleus of BV2 microglia. Translocated IRF2 activates KLF4 transcription, increasing CD206-positive (M2) microglia cells.","method":"Protein microarray binding screen, cell treatment with agmatine, nuclear translocation assay, flow cytometry","journal":"Inflammation research","confidence":"Medium","confidence_rationale":"Tier 3 — protein microarray binding with functional follow-up, single lab","pmids":["37314519"],"is_preprint":false},{"year":2024,"finding":"IRF2BP2 interacts with the AP-1 heterodimer ATF7/JDP2, is recruited by this dimer to chromatin, and counteracts its gene-activating function. Loss of IRF2BP2 leads to overactivation of inflammatory pathways and strongly reduced AML cell proliferation, defining a pro-oncogenic inflammatory equilibrium maintained by the ATF7/JDP2-IRF2BP2 regulatory axis.","method":"Co-immunoprecipitation, ChIP, siRNA/KO loss-of-function, transcriptomic analysis in AML cells","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ChIP, and functional KO with defined cellular phenotype; moderate evidence","pmids":["38801077"],"is_preprint":false},{"year":2024,"finding":"Structural and biochemical studies revealed that the RING domain of IRF2BP2 binds a conserved RxSVI motif present in IRF2, VGLL4, and ZBTB16. The motif-containing peptides form a short loop and β-strand recognized by the RING domain. IRF2BP2 regulates megakaryocytic differentiation through its interaction with ZBTB16 via this RxSVI motif.","method":"Motif discovery, X-ray crystallography/structural analysis, biochemical binding assays, cell biological differentiation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — structural data + biochemical binding + functional cell differentiation assay","pmids":["39616187"],"is_preprint":false},{"year":2024,"finding":"In T-ALL cells, IRF2BP2 is driven by a super-enhancer activated by master transcription factors ERG, ELF1, and ETS1. IRF2BP2 cooperates with master TFs to target the enhancer of the RAG1 gene and modulate its expression. Loss of IRF2BP2 affects MYC and E2F pathways. Hematopoietic-specific IRF2BP2 knockout mice showed minimal impact on normal T cell development but IRF2BP2 was crucial for T-ALL cell growth and survival in vitro and in vivo.","method":"CUT&Tag, immunoprecipitation, conditional KO mice, in vitro and in vivo T-ALL growth assays, transcriptomic analysis","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 — CUT&Tag + IP + conditional KO with in vivo rescue, multiple orthogonal methods","pmids":["39454110"],"is_preprint":false},{"year":2024,"finding":"In neuroblastoma, super-enhancer-driven IRF2BP2 is activated by master transcription factors MYCN, MEIS2, and HAND2. AP-1 family proteins shape chromatin accessibility to expose IRF2BP2 binding sites, enabling AP-1 and IRF2BP2 to collaboratively stimulate expression of the ALK susceptibility gene, thereby maintaining the highly proliferative NB phenotype.","method":"ChIP-seq, chromatin accessibility analysis, transcriptome sequencing, loss-of-function experiments, in vivo xenograft models","journal":"Neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP-seq and transcriptomic evidence with functional KO, single lab","pmids":["38864832"],"is_preprint":false},{"year":2025,"finding":"IRF2BP2 directly represses lipolysis-related genes including LIPE (encoding hormone sensitive lipase) in adipocytes, as shown by ChIP-seq demonstrating direct promoter binding. Adipocyte-selective Irf2bp2 deletion in mice increased Lipe expression and free fatty acid levels, causing adipose tissue inflammation and glucose intolerance.","method":"RNA-seq, ChIP-seq, adipocyte-specific conditional KO mice, primary human adipocyte KO and OE","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1/2 — ChIP-seq + RNA-seq + adipocyte-specific KO in mice + human cell validation","pmids":["39752494"],"is_preprint":false},{"year":2025,"finding":"In ven/aza-resistant AML, MCL1 was identified as an IRF2BP2 binding partner by co-immunoprecipitation and mass spectrometry. This MCL1-IRF2BP2 interaction results in cytoplasmic sequestration of IRF2BP2, causing loss of transcriptional repression and increased expression of IRF2BP2 target gene ACSL1, an enzyme required for fatty acid oxidation. Inhibition of ACSL1 impaired ven/aza-resistant leukemic stem cells.","method":"Co-IP + mass spectrometry, subcellular fractionation, ACSL1 inhibition functional assay, metabolite profiling","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP/MS identification, subcellular localization with functional consequence, ACSL1 rescue; preprint, single lab","pmids":["40475530"],"is_preprint":true},{"year":2025,"finding":"IRF2BP2 cooperates with TRIM28 and DNMT1 to epigenetically silence transposable elements (TEs), particularly HERV-K/LTR5_Hs, in AML cells. Loss of IRF2BP2 induced differentiation, apoptosis, and TE transcriptional activation. CRISPR-mediated activation of HERV-K/LTR5_Hs recapitulated IRF2BP2 loss phenotypes, and re-silencing of HERV-K partially rescued these effects.","method":"Single-cell Perturb-seq screen, CRISPR activation/silencing, co-immunoprecipitation, AML patient primary cells","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — Perturb-seq screen, CRISPR activation/rescue, Co-IP for complex; preprint, single lab","pmids":[],"is_preprint":true},{"year":2025,"finding":"The IRF2BP2::JAK2 fusion protein localizes to the cytoplasm and drives constitutive JAK-STAT signaling, conferring cytokine-independent growth in Ba/F3 cells engineered by CRISPR-Cas9 to express the fusion. Both type I (ruxolitinib) and type II (CHZ868) JAK inhibitors potently inhibited this fusion kinase.","method":"CRISPR-Cas9 genome engineering of Ba/F3 cells, cytokine-independent growth assay, JAK inhibitor treatment, subcellular localization","journal":"Genes, chromosomes & cancer","confidence":"High","confidence_rationale":"Tier 1 — reconstituted fusion in Ba/F3 cells with functional readout, inhibitor validation, direct localization","pmids":["41711169"],"is_preprint":false},{"year":2024,"finding":"Variants in the C-terminal RING finger domain of IRF2BP2 caused irregular aggregate formation and non-nuclear distribution, while N-terminal zinc finger domain variants retained normal nuclear localization. Immunoblotting revealed impaired IRF2 and NFκB1 (p50) nuclear localization in IRF2BP2 mutants compared to wild-type, indicating that IRF2BP2 controls nuclear translocation of both IRF2 and NF-κB.","method":"Confocal fluorescence microscopy, Western blotting, overexpression of EGFP-fused mutants in HEK293 cells","journal":"Clinical immunology","confidence":"Medium","confidence_rationale":"Tier 3 — localization and Western blot analysis, single lab, moderate evidence","pmids":["39059757"],"is_preprint":false},{"year":2022,"finding":"Irf2bp2 is required for fetal hepatic erythropoiesis through the expansion of erythromyeloid progenitors. Germline ablation of Irf2bp2 caused near-complete lethality with predominantly upregulation of interferon-responsive genes and elevation of hematopoietic stem cell-enriched transcription factors (Etv6, Fli1, Ikzf1, Runx1) in Irf2bp2-null livers.","method":"Germline KO mice, transcriptome profiling (liver, heart, skeletal muscle), FISH for chimerism","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with transcriptomic profiling and defined phenotypic readout, single lab","pmids":["35865523"],"is_preprint":false}],"current_model":"IRF2BP2 is a nuclear transcriptional co-repressor/co-activator whose RING domain binds a conserved RxSVI motif in partner proteins (including IRF2, VGLL4, ZBTB16, and NFAT1), enabling it to suppress inflammatory signaling (via NF-κB, NFAT1, STAT1, and AP-1/ATF7-JDP2 pathways), regulate metabolic gene expression (ATF3 in liver steatosis, LIPE in adipocyte lipolysis, ACSL1 in AML), control cell differentiation (erythropoiesis, megakaryopoiesis, osteoclast/osteoblast balance, B- and T-cell maturation), and activate VEGFA expression through the TEAD4/VGLL4 complex; its cytoplasmic sequestration by MCL1 in drug-resistant AML or its post-transcriptional suppression by miR-155-5p represent mechanisms that derepress its target genes and drive pathological states."},"narrative":{"teleology":[{"year":2008,"claim":"Establishing IRF2BP2 as a p53-responsive transcriptional modulator answered how cells fine-tune p53-mediated apoptosis and cell-cycle arrest, revealing a feedback loop in which p53 induces its own co-repressor.","evidence":"Luciferase reporters, siRNA knockdown, and overexpression in multiple cell lines treated with actinomycin D/doxorubicin","pmids":["19042971"],"confidence":"High","gaps":["Direct chromatin occupancy at p21/Bax promoters not demonstrated","Physiological relevance in vivo not tested","Mechanism of repression (corepressor recruitment vs. direct interference) unresolved"]},{"year":2010,"claim":"Identifying IRF2BP2 as a component of the TEAD4/VGLL4 complex that activates VEGFA expression established that IRF2BP2 can function as a transcriptional co-activator, not solely a repressor.","evidence":"Yeast two-hybrid from human heart library, reciprocal Co-IP, mammalian two-hybrid, siRNA knockdown in C2C12 cells","pmids":["20702774"],"confidence":"High","gaps":["Mechanism by which IRF2BP2 switches from repressor to activator function unknown","In vivo vascular phenotype not assessed"]},{"year":2015,"claim":"Conditional knockout in macrophages demonstrated that IRF2BP2 is required for MEF2-dependent KLF2 activation, linking it to cholesterol efflux and anti-inflammatory macrophage polarization—the first in vivo loss-of-function evidence for its immune-regulatory role.","evidence":"Macrophage-specific conditional KO mice, luciferase promoter assays, cholesterol efflux assays, KLF2 genetic rescue","pmids":["26195219"],"confidence":"High","gaps":["Whether IRF2BP2 directly contacts MEF2 at the KLF2 promoter not shown by ChIP","Upstream signals regulating IRF2BP2 expression in macrophages unclear"]},{"year":2017,"claim":"Two studies established IRF2BP2 as a critical anti-inflammatory and cardioprotective factor: cardiomyocyte-specific KO proved IRF2BP2 restrains NFAT1-driven hypertrophy, while microglia-specific KO showed it mediates IFNβ-dependent neuroprotection after stroke.","evidence":"Cardiomyocyte- and microglia-specific conditional KO and transgenic OE mice, Co-IP of IRF2BP2-NFAT1, epistasis rescue by NFAT1 blockade, photothrombotic stroke model","pmids":["28716987","28769762"],"confidence":"High","gaps":["Structural basis of IRF2BP2-NFAT1 interaction unresolved at the time","Whether cardiac and microglial mechanisms share a common IRF2BP2-dependent chromatin program unknown"]},{"year":2019,"claim":"Three discoveries expanded IRF2BP2's mechanistic repertoire: its RING domain sequesters repressive activity via VGLL4 binding in erythropoiesis, it co-regulates glucocorticoid receptor–NF-κB crosstalk genome-wide, and the IRF2BP2/KLF2 axis controls osteoclast-osteoblast balance.","evidence":"CRISPR KO zebrafish with epistasis rescue (VGLL4-IRF2BP2-alas2), ChIP-seq in A549 cells for GR/IRF2BP2 co-binding, overexpression/KD in osteoclast precursor and osteoblast differentiation assays","pmids":["31539803","31145973","31186082"],"confidence":"High","gaps":["Human erythropoiesis relevance of VGLL4-IRF2BP2 axis not tested","Whether GR directly recruits IRF2BP2 or they co-bind independently unclear","Osteoclast data based on overexpression only, no KO"]},{"year":2020,"claim":"ChIP-seq identification of ATF3 as a direct IRF2BP2 target gene in hepatocytes, combined with hepatocyte-specific KO exacerbating steatosis, established IRF2BP2 as a metabolic gatekeeper in liver lipid homeostasis.","evidence":"Hepatocyte-specific conditional KO and AAV overexpression in HFD-fed mice, ChIP-seq, luciferase assay, ATF3 siRNA rescue","pmids":["31529495"],"confidence":"High","gaps":["Whether IRF2BP2 represses ATF3 via E3 ligase activity or corepressor recruitment unresolved","Human liver disease correlation not established"]},{"year":2022,"claim":"Identifying IRF2BP2 as an HNF4α co-repressor whose activity depends on E3 ubiquitin ligase function, and demonstrating that germline Irf2bp2 KO is near-lethal due to failed fetal erythropoiesis, defined IRF2BP2 as essential for development and revealed a catalytic mechanism for its repressive function.","evidence":"Novel proteomic detection of labile HNF4α interaction, E3 ligase domain mutant analysis, germline KO mice with transcriptomic profiling of fetal liver","pmids":["35609419","35865523"],"confidence":"Medium","gaps":["E3 ubiquitin ligase substrates not identified","HNF4α interaction detected by novel method only, not by conventional Co-IP","Cause of lethality (erythroid vs. cardiac vs. combined) not fully dissected"]},{"year":2024,"claim":"Structural resolution of the RING domain bound to the RxSVI motif of IRF2, VGLL4, and ZBTB16 unified the molecular basis for IRF2BP2's diverse partnerships and linked the ZBTB16 interaction to megakaryocytic differentiation.","evidence":"X-ray crystallography/structural analysis, biochemical binding assays, megakaryocyte differentiation assays","pmids":["39616187"],"confidence":"High","gaps":["Whether all cellular partners use the same RxSVI motif or alternative interfaces exist unknown","No full-length IRF2BP2 structure available"]},{"year":2024,"claim":"Context-dependent oncogenic roles were established: in T-ALL, super-enhancer-driven IRF2BP2 sustains MYC/E2F programs and is essential for leukemic growth; in neuroblastoma, AP-1 cooperates with IRF2BP2 to activate ALK expression; and in AML, IRF2BP2 counteracts ATF7/JDP2-driven inflammatory gene activation to maintain proliferation.","evidence":"CUT&Tag, ChIP-seq, conditional KO mice for T-ALL, xenograft models for neuroblastoma, Co-IP and ChIP with functional KO in AML cells","pmids":["39454110","38864832","38801077"],"confidence":"High","gaps":["Whether IRF2BP2 is a viable therapeutic target in these cancers not tested with specific inhibitors","Relative contribution of inflammatory suppression vs. TE silencing in AML proliferation unclear"]},{"year":2024,"claim":"Domain-level analysis of human IRF2BP2 variants showed that RING domain mutations cause cytoplasmic aggregation and impair nuclear translocation of both IRF2 and NF-κB1, while a patient mutation (c.625_665del) fails to suppress STAT1, linking IRF2BP2 dysfunction to interferon hyperactivation.","evidence":"Confocal microscopy of EGFP-fused mutants in HEK293, Western blot for nuclear IRF2/NF-κB1, luciferase STAT1 reporter, patient PBMC analysis","pmids":["39059757","34451894"],"confidence":"Medium","gaps":["No Mendelian disease formally defined from these variants","Structural consequences of RING domain mutations not solved","Patient cohort small"]},{"year":2025,"claim":"Adipocyte-specific Irf2bp2 deletion proved that IRF2BP2 directly represses LIPE to restrain lipolysis, with its loss causing adipose inflammation and glucose intolerance, extending the metabolic gatekeeper role from liver to adipose tissue.","evidence":"ChIP-seq, RNA-seq, adipocyte-specific conditional KO mice, primary human adipocyte knockout and overexpression","pmids":["39752494"],"confidence":"High","gaps":["Upstream metabolic signals that regulate IRF2BP2 in adipocytes unknown","Whether hepatic and adipose IRF2BP2 functions are coordinately regulated unclear"]},{"year":2025,"claim":"MCL1-mediated cytoplasmic sequestration of IRF2BP2 in drug-resistant AML derepresses the fatty acid oxidation gene ACSL1, defining a non-transcriptional mechanism of IRF2BP2 inactivation in cancer; separately, IRF2BP2 cooperates with TRIM28/DNMT1 to epigenetically silence transposable elements in AML.","evidence":"(preprint) Co-IP/mass spectrometry for MCL1 interaction, subcellular fractionation, ACSL1 inhibition assay; (preprint) Perturb-seq screen, CRISPR activation/silencing of HERV-K","pmids":["40475530"],"confidence":"Medium","gaps":["Both findings are preprints awaiting peer review","Whether MCL1 sequestration occurs in non-AML contexts unknown","Relative contribution of TE derepression vs. ACSL1 upregulation to AML drug resistance not dissected"]},{"year":null,"claim":"Key unresolved questions include the identity of E3 ubiquitin ligase substrates, whether IRF2BP2's activator vs. repressor switch is determined by partner identity or post-translational modification, and whether pharmacological disruption of the RING-RxSVI interface is therapeutically feasible.","evidence":"","pmids":[],"confidence":"Low","gaps":["No bona fide ubiquitination substrate identified","Molecular switch between co-activator and co-repressor modes uncharacterized","No small-molecule modulator of IRF2BP2 reported"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,2,4,7,9,14,16]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,11,14]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,7,9,14,15,22]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[19,22]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,2,7,9,14,16,17,18]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,3,5,10,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,11,21]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[9,12,18]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8,15,23]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[20]}],"complexes":["TEAD4/VGLL4/IRF2BP2","IRF2BP2/TRIM28/DNMT1","ATF7/JDP2/IRF2BP2"],"partners":["IRF2","VGLL4","NFAT1","ZBTB16","TEAD4","HNF4A","MCL1","TRIM28"],"other_free_text":[]},"mechanistic_narrative":"IRF2BP2 is a nuclear transcriptional co-repressor that uses its RING domain to recognize a conserved RxSVI motif in diverse partner proteins—including IRF2, VGLL4, ZBTB16, and NFAT1—thereby modulating inflammatory, metabolic, and differentiation programs across multiple tissues [PMID:39616187, PMID:28716987]. In macrophages and microglia, IRF2BP2 activates KLF2 expression through MEF2 and suppresses NF-κB, STAT1, and AP-1/ATF7-JDP2 inflammatory signaling; its loss causes exaggerated inflammatory responses, impaired cholesterol efflux, and worsened stroke outcomes [PMID:26195219, PMID:28769762, PMID:38801077]. IRF2BP2 directly represses metabolic target genes such as ATF3 in hepatocytes and LIPE in adipocytes, and its hepatocyte- or adipocyte-specific deletion exacerbates hepatic steatosis or adipose inflammation, respectively [PMID:31529495, PMID:39752494]. In hematopoiesis, IRF2BP2 is essential for fetal erythropoiesis and megakaryocytic differentiation, cooperates with TRIM28/DNMT1 to silence transposable elements in AML, and is required for T-ALL cell survival through super-enhancer-driven regulation of MYC/E2F pathways [PMID:35865523, PMID:39616187, PMID:39454110]."},"prefetch_data":{"uniprot":{"accession":"Q7Z5L9","full_name":"Interferon regulatory factor 2-binding protein 2","aliases":[],"length_aa":587,"mass_kda":61.0,"function":"Acts as a transcriptional corepressor in a IRF2-dependent manner; this repression is not mediated by histone deacetylase activities (PubMed:12799427). Represses the NFAT1-dependent transactivation of NFAT-responsive promoters (PubMed:21576369). Acts as a coactivator of VEGFA expression in cardiac and skeletal muscles (PubMed:20702774). Plays a role in immature B-cell differentiation (PubMed:27016798)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q7Z5L9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IRF2BP2","classification":"Not Classified","n_dependent_lines":192,"n_total_lines":1208,"dependency_fraction":0.15894039735099338},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IRF2BP2","total_profiled":1310},"omim":[{"mim_id":"621027","title":"CHOLESTEROL-INDUCED REGULATOR OF METABOLISM RNA, NONCODING; CHROMR","url":"https://www.omim.org/entry/621027"},{"mim_id":"617765","title":"IMMUNODEFICIENCY, COMMON VARIABLE, 14; CVID14","url":"https://www.omim.org/entry/617765"},{"mim_id":"615332","title":"INTERFERON REGULATORY FACTOR 2-BINDING PROTEIN 2; IRF2BP2","url":"https://www.omim.org/entry/615332"},{"mim_id":"615331","title":"INTERFERON REGULATORY FACTOR 2-BINDING PROTEIN 1; IRF2BP1","url":"https://www.omim.org/entry/615331"},{"mim_id":"607594","title":"IMMUNODEFICIENCY, COMMON VARIABLE, 1; CVID1","url":"https://www.omim.org/entry/607594"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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Coexpression of IRF2BP2 with TEAD4/VGLL4 or TEAD1 potently activated VEGFA expression, while knockdown of IRF2BP2 reduced VEGFA expression in C2C12 muscle cells.\",\n      \"method\": \"Yeast 2-hybrid, coimmunoprecipitation, mammalian 2-hybrid, siRNA knockdown\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and functional KD with defined gene expression readout, moderate evidence\",\n      \"pmids\": [\"20702774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IRF2BP2 was identified as a direct transcriptional target of p53. Upregulation of IRF2BP2 after actinomycin D treatment is p53-dependent. Overexpressed IRF2BP2 impedes p53-mediated transactivation of p21 and Bax genes. Knockdown of IRF2BP2 leads to upregulation of p21 and faster induction of apoptosis after doxorubicin or actinomycin D treatment, indicating IRF2BP2 modulates cell survival decisions during p53 stress response.\",\n      \"method\": \"Luciferase reporter assay, siRNA knockdown, overexpression in multiple cell lines, actinomycin D/doxorubicin treatment\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (reporter, KD, OE) with defined phenotypic readout in multiple cell lines\",\n      \"pmids\": [\"19042971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IRF2BP2 is required for MEF2-dependent activation of KLF2 (Krüppel-like factor 2) in macrophages. Promoter studies revealed this dependence. IRF2BP2-deficient macrophages have markedly reduced KLF2 expression, impaired cholesterol efflux due to inability to activate ABCA1, and increased M1 inflammatory activation. Restoring KLF2 in IRF2BP2-deficient macrophages rescued these defects.\",\n      \"method\": \"Macrophage-specific conditional knockout mice, promoter/luciferase assay, cholesterol efflux assay, genetic rescue experiment\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with multiple orthogonal functional readouts and rescue experiment, replicated in vivo\",\n      \"pmids\": [\"26195219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Ectopic expression of IRF2BP2 in murine primary CD4 T cells reduced CD25 expression, STAT5 phosphorylation, CD69 expression, and impaired proliferative capacity. In vivo, IRF2BP2-overexpressing transferred cells displayed impaired expansion, establishing IRF2BP2 as a repressor of naive CD4 T cell activation and clonal expansion downstream of TCR triggering.\",\n      \"method\": \"Retroviral transduction of primary murine CD4 T cells, in vivo adoptive transfer, flow cytometry, phospho-STAT5 analysis\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean OE with defined cellular phenotype in vitro and in vivo, single lab\",\n      \"pmids\": [\"27286791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IRF2BP2 directly interacted with the C-terminal transactivation domain of NFAT1, competing with MEF2C and disturbing their transcriptional synergism, thereby inhibiting NFAT1-transactivated hypertrophic transcriptome. Cardiomyocyte-specific Irf2bp2 knockout exacerbated aortic banding- and angiotensin II-induced cardiac hypertrophy, while Irf2bp2 transgenic overexpression was protective. The effect of Irf2bp2 deficiency was rescued by NFAT1 blockade.\",\n      \"method\": \"Cardiomyocyte-specific conditional KO and transgenic overexpression mice, Co-IP, epistasis rescue by NFAT1 blockade, aortic banding/angiotensin II models\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO, transgenic OE, direct protein interaction, epistasis rescue; multiple orthogonal methods\",\n      \"pmids\": [\"28716987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Loss of IRF2BP2 in microglia leads to increased inflammatory cytokine expression in response to LPS and impaired anti-inflammatory marker activation in response to IL-4. IRF2BP2-deficient mice had larger brain infarctions after photothrombotic stroke with fewer anti-inflammatory M2 microglia. IRF2BP2 also mediates the anti-inflammatory and neuroprotective effect of IFNβ, which was lost in IRF2BP2-deficient macrophages.\",\n      \"method\": \"Macrophage/microglia-specific conditional KO mice, photothrombosis stroke model, LPS/IL-4 stimulation, cytokine measurement, IFNβ treatment\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined in vivo and in vitro phenotypic readouts, epistasis with IFNβ\",\n      \"pmids\": [\"28769762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IRF2BP2 overexpression suppresses osteoclast differentiation and enhances osteoblast differentiation; these effects were reversed by KLF2 knockdown, establishing the IRF2BP2/KLF2 axis as a regulator of osteoclast and osteoblast differentiation.\",\n      \"method\": \"Overexpression and siRNA knockdown in osteoclast precursor cells and osteoblasts, differentiation assays, marker gene expression\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis with KLF2 rescue, single lab\",\n      \"pmids\": [\"31186082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IRF2BP2 modulates glucocorticoid receptor (GR) and NF-κB transcriptional activity. GC treatment changes chromatin binding of IRF2BP2, with IRF2BP2-binding sites co-occurring with GR binding sites. Depletion of IRF2BP2 modulates transcription of GC-regulated genes and alters responses to both glucocorticoids and TNF in A549 cells, positioning IRF2BP2 as a coregulator of GR-NF-κB crosstalk.\",\n      \"method\": \"ChIP-seq, siRNA knockdown, transcriptomic analysis in HEK293 and A549 cells\",\n      \"journal\": \"Journal of steroid biochemistry and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq + KD with transcriptomic readout, single lab, moderate evidence\",\n      \"pmids\": [\"31145973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In zebrafish, VGLL4 sequesters IRF2BP2 via the VGLL4 TDU1 and IRF2BP2 RING finger domains, thereby inhibiting IRF2BP2's repression of alas2 (aminolevulinate synthase 2) expression and heme biosynthesis. IRF2BP2 depletion rescued impaired erythroid terminal differentiation in vgll4b-deficient zebrafish, establishing an oxygen-sensing pathway: NOTCH1→HIF1α→VGLL4→IRF2BP2→alas2.\",\n      \"method\": \"CRISPR/Cas9 knockout zebrafish, genetic epistasis rescue (irf2bp2 depletion rescuing vgll4b mutant), domain-mapping experiments\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with epistasis rescue, domain-level mechanism, ortholog (zebrafish)\",\n      \"pmids\": [\"31539803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IRF2BP2 directly binds the promoter region of ATF3 (activating transcription factor 3) as a transcriptional repressor, as demonstrated by ChIP-seq and luciferase assay. Hepatocyte-specific Irf2bp2 knockout exacerbated high-fat diet-induced hepatic steatosis, while Irf2bp2 overexpression was protective. ATF3 knockdown significantly relieved IRF2BP2 knockout-exaggerated hepatosteatosis in vitro.\",\n      \"method\": \"Hepatocyte-specific conditional KO and adeno-associated virus overexpression in mice, ChIP-seq, luciferase assay, digital gene expression, ATF3 siRNA rescue\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — ChIP-seq + luciferase + genetic epistasis rescue, multiple orthogonal methods\",\n      \"pmids\": [\"31529495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-155-5p targets IRF2BP2 mRNA (validated by luciferase reporter assay). Immunoprecipitation showed that IRF2BP2 binds NFAT1, and oroxylin A increases this binding, reducing iNOS-driven inflammation. shRNA knockdown of miR-155-5p in bone marrow ameliorated LPS-induced acute lung injury in mice.\",\n      \"method\": \"Luciferase reporter assay, immunoprecipitation, shRNA in vivo, LPS-induced lung injury mouse model\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP and reporter assay showing IRF2BP2-NFAT1 interaction, single lab\",\n      \"pmids\": [\"33052070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IRF2BP2 is required to attenuate STAT1 transcriptional activity; IRF2BP2 c.625_665del mutation failed to suppress STAT1 transcriptional activity in a luciferase reporter system. Patient cells with this mutation showed overexpression of STAT1 protein and increased constitutive activation of STAT1 and STAT5, as well as elevated interferon-inducible gene expression.\",\n      \"method\": \"Luciferase reporter system, flow cytometry (phospho-STAT), patient PBMC analysis, NanoString gene expression\",\n      \"journal\": \"Pharmaceuticals\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — reporter assay + patient cell analysis; single lab, moderate evidence\",\n      \"pmids\": [\"34451894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IRF2BP2 was identified as a novel HNF4α co-repressor. This interaction could not be detected by conventional immunoprecipitation but was identified through novel proteomic techniques sensitive to biochemically labile interactions. IRF2BP2 repressed HNF4α transcriptional activity dependent on its E3 ubiquitin ligase activity. IRF2BP2 deficiency in HepG2 cells induced gluconeogenic genes comparable to forskolin-treated wild-type cells.\",\n      \"method\": \"Novel proteomic approach for biochemically labile interactions, luciferase reporter assay, IRF2BP2 gene deletion in HepG2 cells, E3 ubiquitin ligase domain mutant\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1/2 — novel proteomic identification, reporter assay, mutant analysis; single lab\",\n      \"pmids\": [\"35609419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Agmatine binds directly to IRF2BP2 (identified by protein microarray). This competitive binding frees IRF2BP2-bound IRF2, allowing free IRF2 to translocate to the nucleus of BV2 microglia. Translocated IRF2 activates KLF4 transcription, increasing CD206-positive (M2) microglia cells.\",\n      \"method\": \"Protein microarray binding screen, cell treatment with agmatine, nuclear translocation assay, flow cytometry\",\n      \"journal\": \"Inflammation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — protein microarray binding with functional follow-up, single lab\",\n      \"pmids\": [\"37314519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IRF2BP2 interacts with the AP-1 heterodimer ATF7/JDP2, is recruited by this dimer to chromatin, and counteracts its gene-activating function. Loss of IRF2BP2 leads to overactivation of inflammatory pathways and strongly reduced AML cell proliferation, defining a pro-oncogenic inflammatory equilibrium maintained by the ATF7/JDP2-IRF2BP2 regulatory axis.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA/KO loss-of-function, transcriptomic analysis in AML cells\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ChIP, and functional KO with defined cellular phenotype; moderate evidence\",\n      \"pmids\": [\"38801077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Structural and biochemical studies revealed that the RING domain of IRF2BP2 binds a conserved RxSVI motif present in IRF2, VGLL4, and ZBTB16. The motif-containing peptides form a short loop and β-strand recognized by the RING domain. IRF2BP2 regulates megakaryocytic differentiation through its interaction with ZBTB16 via this RxSVI motif.\",\n      \"method\": \"Motif discovery, X-ray crystallography/structural analysis, biochemical binding assays, cell biological differentiation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural data + biochemical binding + functional cell differentiation assay\",\n      \"pmids\": [\"39616187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In T-ALL cells, IRF2BP2 is driven by a super-enhancer activated by master transcription factors ERG, ELF1, and ETS1. IRF2BP2 cooperates with master TFs to target the enhancer of the RAG1 gene and modulate its expression. Loss of IRF2BP2 affects MYC and E2F pathways. Hematopoietic-specific IRF2BP2 knockout mice showed minimal impact on normal T cell development but IRF2BP2 was crucial for T-ALL cell growth and survival in vitro and in vivo.\",\n      \"method\": \"CUT&Tag, immunoprecipitation, conditional KO mice, in vitro and in vivo T-ALL growth assays, transcriptomic analysis\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CUT&Tag + IP + conditional KO with in vivo rescue, multiple orthogonal methods\",\n      \"pmids\": [\"39454110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In neuroblastoma, super-enhancer-driven IRF2BP2 is activated by master transcription factors MYCN, MEIS2, and HAND2. AP-1 family proteins shape chromatin accessibility to expose IRF2BP2 binding sites, enabling AP-1 and IRF2BP2 to collaboratively stimulate expression of the ALK susceptibility gene, thereby maintaining the highly proliferative NB phenotype.\",\n      \"method\": \"ChIP-seq, chromatin accessibility analysis, transcriptome sequencing, loss-of-function experiments, in vivo xenograft models\",\n      \"journal\": \"Neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq and transcriptomic evidence with functional KO, single lab\",\n      \"pmids\": [\"38864832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IRF2BP2 directly represses lipolysis-related genes including LIPE (encoding hormone sensitive lipase) in adipocytes, as shown by ChIP-seq demonstrating direct promoter binding. Adipocyte-selective Irf2bp2 deletion in mice increased Lipe expression and free fatty acid levels, causing adipose tissue inflammation and glucose intolerance.\",\n      \"method\": \"RNA-seq, ChIP-seq, adipocyte-specific conditional KO mice, primary human adipocyte KO and OE\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — ChIP-seq + RNA-seq + adipocyte-specific KO in mice + human cell validation\",\n      \"pmids\": [\"39752494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In ven/aza-resistant AML, MCL1 was identified as an IRF2BP2 binding partner by co-immunoprecipitation and mass spectrometry. This MCL1-IRF2BP2 interaction results in cytoplasmic sequestration of IRF2BP2, causing loss of transcriptional repression and increased expression of IRF2BP2 target gene ACSL1, an enzyme required for fatty acid oxidation. Inhibition of ACSL1 impaired ven/aza-resistant leukemic stem cells.\",\n      \"method\": \"Co-IP + mass spectrometry, subcellular fractionation, ACSL1 inhibition functional assay, metabolite profiling\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP/MS identification, subcellular localization with functional consequence, ACSL1 rescue; preprint, single lab\",\n      \"pmids\": [\"40475530\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IRF2BP2 cooperates with TRIM28 and DNMT1 to epigenetically silence transposable elements (TEs), particularly HERV-K/LTR5_Hs, in AML cells. Loss of IRF2BP2 induced differentiation, apoptosis, and TE transcriptional activation. CRISPR-mediated activation of HERV-K/LTR5_Hs recapitulated IRF2BP2 loss phenotypes, and re-silencing of HERV-K partially rescued these effects.\",\n      \"method\": \"Single-cell Perturb-seq screen, CRISPR activation/silencing, co-immunoprecipitation, AML patient primary cells\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Perturb-seq screen, CRISPR activation/rescue, Co-IP for complex; preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The IRF2BP2::JAK2 fusion protein localizes to the cytoplasm and drives constitutive JAK-STAT signaling, conferring cytokine-independent growth in Ba/F3 cells engineered by CRISPR-Cas9 to express the fusion. Both type I (ruxolitinib) and type II (CHZ868) JAK inhibitors potently inhibited this fusion kinase.\",\n      \"method\": \"CRISPR-Cas9 genome engineering of Ba/F3 cells, cytokine-independent growth assay, JAK inhibitor treatment, subcellular localization\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted fusion in Ba/F3 cells with functional readout, inhibitor validation, direct localization\",\n      \"pmids\": [\"41711169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Variants in the C-terminal RING finger domain of IRF2BP2 caused irregular aggregate formation and non-nuclear distribution, while N-terminal zinc finger domain variants retained normal nuclear localization. Immunoblotting revealed impaired IRF2 and NFκB1 (p50) nuclear localization in IRF2BP2 mutants compared to wild-type, indicating that IRF2BP2 controls nuclear translocation of both IRF2 and NF-κB.\",\n      \"method\": \"Confocal fluorescence microscopy, Western blotting, overexpression of EGFP-fused mutants in HEK293 cells\",\n      \"journal\": \"Clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — localization and Western blot analysis, single lab, moderate evidence\",\n      \"pmids\": [\"39059757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Irf2bp2 is required for fetal hepatic erythropoiesis through the expansion of erythromyeloid progenitors. Germline ablation of Irf2bp2 caused near-complete lethality with predominantly upregulation of interferon-responsive genes and elevation of hematopoietic stem cell-enriched transcription factors (Etv6, Fli1, Ikzf1, Runx1) in Irf2bp2-null livers.\",\n      \"method\": \"Germline KO mice, transcriptome profiling (liver, heart, skeletal muscle), FISH for chimerism\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with transcriptomic profiling and defined phenotypic readout, single lab\",\n      \"pmids\": [\"35865523\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IRF2BP2 is a nuclear transcriptional co-repressor/co-activator whose RING domain binds a conserved RxSVI motif in partner proteins (including IRF2, VGLL4, ZBTB16, and NFAT1), enabling it to suppress inflammatory signaling (via NF-κB, NFAT1, STAT1, and AP-1/ATF7-JDP2 pathways), regulate metabolic gene expression (ATF3 in liver steatosis, LIPE in adipocyte lipolysis, ACSL1 in AML), control cell differentiation (erythropoiesis, megakaryopoiesis, osteoclast/osteoblast balance, B- and T-cell maturation), and activate VEGFA expression through the TEAD4/VGLL4 complex; its cytoplasmic sequestration by MCL1 in drug-resistant AML or its post-transcriptional suppression by miR-155-5p represent mechanisms that derepress its target genes and drive pathological states.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IRF2BP2 is a nuclear transcriptional co-repressor that uses its RING domain to recognize a conserved RxSVI motif in diverse partner proteins—including IRF2, VGLL4, ZBTB16, and NFAT1—thereby modulating inflammatory, metabolic, and differentiation programs across multiple tissues [PMID:39616187, PMID:28716987]. In macrophages and microglia, IRF2BP2 activates KLF2 expression through MEF2 and suppresses NF-κB, STAT1, and AP-1/ATF7-JDP2 inflammatory signaling; its loss causes exaggerated inflammatory responses, impaired cholesterol efflux, and worsened stroke outcomes [PMID:26195219, PMID:28769762, PMID:38801077]. IRF2BP2 directly represses metabolic target genes such as ATF3 in hepatocytes and LIPE in adipocytes, and its hepatocyte- or adipocyte-specific deletion exacerbates hepatic steatosis or adipose inflammation, respectively [PMID:31529495, PMID:39752494]. In hematopoiesis, IRF2BP2 is essential for fetal erythropoiesis and megakaryocytic differentiation, cooperates with TRIM28/DNMT1 to silence transposable elements in AML, and is required for T-ALL cell survival through super-enhancer-driven regulation of MYC/E2F pathways [PMID:35865523, PMID:39616187, PMID:39454110].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing IRF2BP2 as a p53-responsive transcriptional modulator answered how cells fine-tune p53-mediated apoptosis and cell-cycle arrest, revealing a feedback loop in which p53 induces its own co-repressor.\",\n      \"evidence\": \"Luciferase reporters, siRNA knockdown, and overexpression in multiple cell lines treated with actinomycin D/doxorubicin\",\n      \"pmids\": [\"19042971\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct chromatin occupancy at p21/Bax promoters not demonstrated\", \"Physiological relevance in vivo not tested\", \"Mechanism of repression (corepressor recruitment vs. direct interference) unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identifying IRF2BP2 as a component of the TEAD4/VGLL4 complex that activates VEGFA expression established that IRF2BP2 can function as a transcriptional co-activator, not solely a repressor.\",\n      \"evidence\": \"Yeast two-hybrid from human heart library, reciprocal Co-IP, mammalian two-hybrid, siRNA knockdown in C2C12 cells\",\n      \"pmids\": [\"20702774\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which IRF2BP2 switches from repressor to activator function unknown\", \"In vivo vascular phenotype not assessed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Conditional knockout in macrophages demonstrated that IRF2BP2 is required for MEF2-dependent KLF2 activation, linking it to cholesterol efflux and anti-inflammatory macrophage polarization—the first in vivo loss-of-function evidence for its immune-regulatory role.\",\n      \"evidence\": \"Macrophage-specific conditional KO mice, luciferase promoter assays, cholesterol efflux assays, KLF2 genetic rescue\",\n      \"pmids\": [\"26195219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IRF2BP2 directly contacts MEF2 at the KLF2 promoter not shown by ChIP\", \"Upstream signals regulating IRF2BP2 expression in macrophages unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Two studies established IRF2BP2 as a critical anti-inflammatory and cardioprotective factor: cardiomyocyte-specific KO proved IRF2BP2 restrains NFAT1-driven hypertrophy, while microglia-specific KO showed it mediates IFNβ-dependent neuroprotection after stroke.\",\n      \"evidence\": \"Cardiomyocyte- and microglia-specific conditional KO and transgenic OE mice, Co-IP of IRF2BP2-NFAT1, epistasis rescue by NFAT1 blockade, photothrombotic stroke model\",\n      \"pmids\": [\"28716987\", \"28769762\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of IRF2BP2-NFAT1 interaction unresolved at the time\", \"Whether cardiac and microglial mechanisms share a common IRF2BP2-dependent chromatin program unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Three discoveries expanded IRF2BP2's mechanistic repertoire: its RING domain sequesters repressive activity via VGLL4 binding in erythropoiesis, it co-regulates glucocorticoid receptor–NF-κB crosstalk genome-wide, and the IRF2BP2/KLF2 axis controls osteoclast-osteoblast balance.\",\n      \"evidence\": \"CRISPR KO zebrafish with epistasis rescue (VGLL4-IRF2BP2-alas2), ChIP-seq in A549 cells for GR/IRF2BP2 co-binding, overexpression/KD in osteoclast precursor and osteoblast differentiation assays\",\n      \"pmids\": [\"31539803\", \"31145973\", \"31186082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human erythropoiesis relevance of VGLL4-IRF2BP2 axis not tested\", \"Whether GR directly recruits IRF2BP2 or they co-bind independently unclear\", \"Osteoclast data based on overexpression only, no KO\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"ChIP-seq identification of ATF3 as a direct IRF2BP2 target gene in hepatocytes, combined with hepatocyte-specific KO exacerbating steatosis, established IRF2BP2 as a metabolic gatekeeper in liver lipid homeostasis.\",\n      \"evidence\": \"Hepatocyte-specific conditional KO and AAV overexpression in HFD-fed mice, ChIP-seq, luciferase assay, ATF3 siRNA rescue\",\n      \"pmids\": [\"31529495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IRF2BP2 represses ATF3 via E3 ligase activity or corepressor recruitment unresolved\", \"Human liver disease correlation not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying IRF2BP2 as an HNF4α co-repressor whose activity depends on E3 ubiquitin ligase function, and demonstrating that germline Irf2bp2 KO is near-lethal due to failed fetal erythropoiesis, defined IRF2BP2 as essential for development and revealed a catalytic mechanism for its repressive function.\",\n      \"evidence\": \"Novel proteomic detection of labile HNF4α interaction, E3 ligase domain mutant analysis, germline KO mice with transcriptomic profiling of fetal liver\",\n      \"pmids\": [\"35609419\", \"35865523\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ubiquitin ligase substrates not identified\", \"HNF4α interaction detected by novel method only, not by conventional Co-IP\", \"Cause of lethality (erythroid vs. cardiac vs. combined) not fully dissected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Structural resolution of the RING domain bound to the RxSVI motif of IRF2, VGLL4, and ZBTB16 unified the molecular basis for IRF2BP2's diverse partnerships and linked the ZBTB16 interaction to megakaryocytic differentiation.\",\n      \"evidence\": \"X-ray crystallography/structural analysis, biochemical binding assays, megakaryocyte differentiation assays\",\n      \"pmids\": [\"39616187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether all cellular partners use the same RxSVI motif or alternative interfaces exist unknown\", \"No full-length IRF2BP2 structure available\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Context-dependent oncogenic roles were established: in T-ALL, super-enhancer-driven IRF2BP2 sustains MYC/E2F programs and is essential for leukemic growth; in neuroblastoma, AP-1 cooperates with IRF2BP2 to activate ALK expression; and in AML, IRF2BP2 counteracts ATF7/JDP2-driven inflammatory gene activation to maintain proliferation.\",\n      \"evidence\": \"CUT&Tag, ChIP-seq, conditional KO mice for T-ALL, xenograft models for neuroblastoma, Co-IP and ChIP with functional KO in AML cells\",\n      \"pmids\": [\"39454110\", \"38864832\", \"38801077\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IRF2BP2 is a viable therapeutic target in these cancers not tested with specific inhibitors\", \"Relative contribution of inflammatory suppression vs. TE silencing in AML proliferation unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Domain-level analysis of human IRF2BP2 variants showed that RING domain mutations cause cytoplasmic aggregation and impair nuclear translocation of both IRF2 and NF-κB1, while a patient mutation (c.625_665del) fails to suppress STAT1, linking IRF2BP2 dysfunction to interferon hyperactivation.\",\n      \"evidence\": \"Confocal microscopy of EGFP-fused mutants in HEK293, Western blot for nuclear IRF2/NF-κB1, luciferase STAT1 reporter, patient PBMC analysis\",\n      \"pmids\": [\"39059757\", \"34451894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No Mendelian disease formally defined from these variants\", \"Structural consequences of RING domain mutations not solved\", \"Patient cohort small\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Adipocyte-specific Irf2bp2 deletion proved that IRF2BP2 directly represses LIPE to restrain lipolysis, with its loss causing adipose inflammation and glucose intolerance, extending the metabolic gatekeeper role from liver to adipose tissue.\",\n      \"evidence\": \"ChIP-seq, RNA-seq, adipocyte-specific conditional KO mice, primary human adipocyte knockout and overexpression\",\n      \"pmids\": [\"39752494\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream metabolic signals that regulate IRF2BP2 in adipocytes unknown\", \"Whether hepatic and adipose IRF2BP2 functions are coordinately regulated unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"MCL1-mediated cytoplasmic sequestration of IRF2BP2 in drug-resistant AML derepresses the fatty acid oxidation gene ACSL1, defining a non-transcriptional mechanism of IRF2BP2 inactivation in cancer; separately, IRF2BP2 cooperates with TRIM28/DNMT1 to epigenetically silence transposable elements in AML.\",\n      \"evidence\": \"(preprint) Co-IP/mass spectrometry for MCL1 interaction, subcellular fractionation, ACSL1 inhibition assay; (preprint) Perturb-seq screen, CRISPR activation/silencing of HERV-K\",\n      \"pmids\": [\"40475530\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Both findings are preprints awaiting peer review\", \"Whether MCL1 sequestration occurs in non-AML contexts unknown\", \"Relative contribution of TE derepression vs. ACSL1 upregulation to AML drug resistance not dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of E3 ubiquitin ligase substrates, whether IRF2BP2's activator vs. repressor switch is determined by partner identity or post-translational modification, and whether pharmacological disruption of the RING-RxSVI interface is therapeutically feasible.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No bona fide ubiquitination substrate identified\", \"Molecular switch between co-activator and co-repressor modes uncharacterized\", \"No small-molecule modulator of IRF2BP2 reported\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2, 4, 7, 9, 14, 16]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 11, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 7, 9, 14, 15, 22]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [19, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 2, 7, 9, 14, 16, 17, 18]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3, 5, 10, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 11, 21]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [9, 12, 18]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 15, 23]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"complexes\": [\n      \"TEAD4/VGLL4/IRF2BP2\",\n      \"IRF2BP2/TRIM28/DNMT1\",\n      \"ATF7/JDP2/IRF2BP2\"\n    ],\n    \"partners\": [\n      \"IRF2\",\n      \"VGLL4\",\n      \"NFAT1\",\n      \"ZBTB16\",\n      \"TEAD4\",\n      \"HNF4A\",\n      \"MCL1\",\n      \"TRIM28\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}