{"gene":"IRF2BP2","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2010,"finding":"IRF2BP2 was identified as a component of the TEAD4/VGLL4 transcription factor complex via yeast 2-hybrid screen from a human heart cDNA library, confirmed in vivo by co-immunoprecipitation and mammalian 2-hybrid assays. Co-expression of IRF2BP2 with TEAD4/VGLL4 or TEAD1 potently activated VEGFA expression, while knockdown reduced VEGFA expression in C2C12 muscle cells.","method":"Yeast 2-hybrid, co-immunoprecipitation, mammalian 2-hybrid, knockdown with gene expression readout","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, mammalian 2-hybrid, and knockdown with functional readout in single study with multiple orthogonal methods","pmids":["20702774"],"is_preprint":false},{"year":2008,"finding":"IRF2BP2 is a direct transcriptional target of p53; its upregulation after actinomycin D treatment is p53-dependent. Overexpressed IRF2BP2 impedes p53-mediated transactivation of p21 and Bax genes, diminishes apoptosis after doxorubicin treatment, and its knockdown leads to upregulation of p21 and faster apoptosis induction.","method":"Reporter assays, loss-of-function (siRNA knockdown), gain-of-function (overexpression), cell viability/apoptosis assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, KD, OE, apoptosis assays) in a single focused study","pmids":["19042971"],"is_preprint":false},{"year":2015,"finding":"IRF2BP2 is required for MEF2-dependent activation of KLF2 (Krüppel-like factor 2) in macrophages, as shown by promoter studies. IRF2BP2-deficient macrophages have markedly reduced KLF2 expression, impaired ABCA1 activation in response to cholesterol loading, and worsened atherosclerosis; restoring KLF2 in IRF2BP2-deficient macrophages rescued anti-inflammatory gene activation and cholesterol efflux.","method":"Macrophage-specific conditional knockout mice, promoter assays, rescue experiments with KLF2 restoration, cholesterol efflux assays","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO in two mouse atherosclerosis models, promoter studies, and rescue experiments with orthogonal readouts","pmids":["26195219"],"is_preprint":false},{"year":2017,"finding":"IRF2BP2 directly interacts with the C-terminal transactivation domain of NFAT1 by competing with MEF2C, disturbing their transcriptional synergism and impeding NFAT1-transactivated hypertrophic transcriptome in cardiomyocytes. Cardiomyocyte-specific Irf2bp2 knockout exacerbated cardiac hypertrophy, while Irf2bp2 transgenic overexpression was protective; the effect of Irf2bp2 deficiency was rescued by NFAT1 blockage.","method":"Cardiomyocyte-specific KO and transgenic mouse models, co-immunoprecipitation of IRF2BP2-NFAT1 interaction, aortic banding and angiotensin II infusion models","journal":"Hypertension","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (NFAT1 blockage rescues KO phenotype), reciprocal interaction assay, and two in vivo KO/transgenic models","pmids":["28716987"],"is_preprint":false},{"year":2016,"finding":"Ectopic expression of IRF2BP2 in murine primary CD4 T cells reduced CD25 expression, STAT5 phosphorylation, and proliferative capacity following TCR stimulation; IRF2BP2-overexpressing cells showed impaired in vivo expansion capacity. IRF2BP2 expression was decreased in CD4 T cells upon activation.","method":"Retroviral transduction of primary CD4 T cells, flow cytometry, in vivo adoptive transfer","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function in primary cells with in vivo validation, but single lab and no direct target gene mechanism identified","pmids":["27286791"],"is_preprint":false},{"year":2016,"finding":"A heterozygous IRF2BP2 mutation (c.1652G>A:p.[S551N]) was identified in a family with CVID. Transduction of mutant IRF2BP2 into control human B cells decreased production of plasmablasts in vitro, demonstrating a role for IRF2BP2 in B-cell differentiation.","method":"Whole-exome sequencing, retroviral transduction into human B cells, in vitro plasmablast differentiation assay, protein immunoblots","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional transduction experiment in primary human B cells, supported by clinical variant, single lab","pmids":["27016798"],"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 macrophages/microglia lost the anti-inflammatory effect of IFNβ, and mice lacking IRF2BP2 in macrophages/microglia showed larger infarctions and worse functional outcomes after photothrombotic stroke.","method":"Conditional macrophage/microglia-specific KO mice, photothrombotic stroke model, cytokine measurements, IFNβ treatment","journal":"Frontiers in cellular neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multiple in vitro and in vivo readouts, IFNβ epistasis experiment, consistent with prior macrophage data","pmids":["28769762"],"is_preprint":false},{"year":2019,"finding":"IRF2BP2 overexpression suppressed osteoclast differentiation and enhanced osteoblast differentiation; these effects were reversed by KLF2 knockdown, establishing an IRF2BP2/KLF2 axis in bone cell differentiation. KLF2 overexpression inhibited osteoclast differentiation by downregulating c-Fos, NFATc1, and TRAP.","method":"Overexpression, siRNA knockdown, osteoclast/osteoblast differentiation assays","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — epistasis via KLF2 rescue experiment, but gain/loss of function only, single lab","pmids":["31186082"],"is_preprint":false},{"year":2019,"finding":"IRF2BP2 modulates glucocorticoid (GC) receptor (GR) and NF-κB signaling: GC changes chromatin binding of IRF2BP2, GC-induced IRF2BP2-binding sites co-occur with GR binding sites and associate with GC-induced genes. Depletion of IRF2BP2 modulates GC-regulated gene transcription and alters responses to both GC and TNFα.","method":"ChIP-seq (chromatin immunoprecipitation sequencing), siRNA depletion, RNA-seq in A549 and HEK293 cells","journal":"The Journal of steroid biochemistry and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and RNA-seq with KD, two orthogonal methods, single lab","pmids":["31145973"],"is_preprint":false},{"year":2019,"finding":"In zebrafish, VGLL4 sequesters IRF2BP2 via their respective TDU1 and RING finger domains, thereby preventing IRF2BP2 from repressing alas2 expression and heme biosynthesis during erythroid terminal differentiation. irf2bp2 depletion rescued the impaired erythroid phenotype of vgll4b mutant zebrafish.","method":"CRISPR/Cas9 vgll4b mutant zebrafish, genetic rescue by irf2bp2 depletion, domain mapping (TDU1/RING finger)","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in zebrafish with domain-level interaction data, single lab","pmids":["31539803"],"is_preprint":false},{"year":2020,"finding":"IRF2BP2 directly represses ATF3 gene expression in hepatocytes by binding to the ATF3 promoter region, as demonstrated by ChIP-seq and luciferase assay. Hepatocyte-specific Irf2bp2 knockout exacerbated high-fat diet-induced hepatic steatosis, insulin resistance and inflammation, while hepatic overexpression was protective; ATF3 knockdown relieved the effects of IRF2BP2 knockout.","method":"Hepatocyte-specific KO and overexpression mouse models, ChIP-seq, luciferase assay, digital gene expression analysis, ATF3 siRNA rescue","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP-seq confirming direct promoter binding, luciferase validation, genetic epistasis via ATF3 KD rescue, in vivo KO and overexpression","pmids":["31529495"],"is_preprint":false},{"year":2020,"finding":"IRF2BP2 binds to NFAT1, and this interaction is increased by the natural compound Oroxylin A. IRF2BP2 binding to NFAT1 was demonstrated by immunoprecipitation assay and is linked to regulation of inducible nitric oxide synthase and inflammatory signaling. miR-155-5p targets IRF2BP2 mRNA (validated by reporter assay), reducing IRF2BP2 levels.","method":"Immunoprecipitation assay, miRNA array, luciferase reporter assay, shRNA injection in mice","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — immunoprecipitation of IRF2BP2-NFAT1 interaction and reporter assay validation of miR-155 targeting, but single lab","pmids":["33052070"],"is_preprint":false},{"year":2021,"finding":"IRF2BP2 is required to attenuate STAT1 transcriptional activity; an IRF2BP2 deletion variant (c.625_665del) failed to suppress STAT1 transcription in a luciferase reporter system. Patients with this mutation showed overexpression and constitutive activation of STAT1, upregulated IFN-JAK-STAT signaling, and elevated STAT5 phosphorylation in CD4+ T cells.","method":"Luciferase reporter assay, flow cytometry for phospho-STAT quantification, NanoString gene expression, clinical patient samples","journal":"Pharmaceuticals","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay mechanistically links IRF2BP2 to STAT1 repression, supported by patient cell data, single lab","pmids":["34451894"],"is_preprint":false},{"year":2022,"finding":"IRF2BP2 represses transcriptional activity of HNF4α and functions as a novel HNF4α co-repressor. The IRF2BP2-HNF4α interaction was detectable only by novel proteomic techniques (not conventional immunoprecipitation). IRF2BP2 repressed HNF4α transcriptional activity in a manner dependent on its E3 ubiquitin ligase activity, and IRF2BP2 gene deficiency in HepG2 cells induced gluconeogenic genes.","method":"Novel proteomic interaction techniques, reporter assay, CRISPR KO of IRF2BP2 in HepG2 cells, gluconeogenic gene expression measurement","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay with E3 ligase mutant and KO cell line; interaction only detectable by specialized proteomics, not conventional IP","pmids":["35609419"],"is_preprint":false},{"year":2024,"finding":"The RING domain of IRF2BP2 binds to a conserved RxSVI motif present in interacting partners IRF2, VGLL4, and ZBTB16. Biochemical and structural data show that motif-containing peptides form a short loop with a short β-strand facilitating RING domain recognition. IRF2BP2 plays a regulatory role in megakaryocytic differentiation through its interaction with ZBTB16.","method":"Motif discovery, biochemical binding assays, structural determination (crystal/NMR), cell biological assays of megakaryocytic differentiation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural data combined with biochemical binding assays and cell biological functional validation in a single rigorous study","pmids":["39616187"],"is_preprint":false},{"year":2024,"finding":"IRF2BP2 interacts with the AP-1 heterodimer ATF7/JDP2 and is recruited to chromatin by this dimer, where it counteracts ATF7/JDP2 gene-activating function. Loss of IRF2BP2 causes overactivation of inflammatory pathways in AML cells, resulting in strongly reduced proliferation.","method":"Co-immunoprecipitation, chromatin recruitment assays, IRF2BP2 loss-of-function in AML cells with RNA-seq","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, chromatin recruitment, and transcriptomic readout with multiple orthogonal methods in a single study","pmids":["38801077"],"is_preprint":false},{"year":2024,"finding":"IRF2BP2 is driven by a super-enhancer in T-ALL regulated by master TFs (ERG, ELF1, ETS1). CUT&Tag and immunoprecipitation show IRF2BP2 cooperates with T-ALL master TFs to target the enhancer of RAG1 and modulate its expression. IRF2BP2 is crucial for T-ALL cell growth and survival in vitro and in vivo, and loss affects MYC and E2F pathways.","method":"CUT&Tag, immunoprecipitation, conditional KO mice (hematopoietic-specific), in vitro and in vivo T-ALL models","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 / Strong — CUT&Tag, IP, conditional KO mice with both in vitro and in vivo validation, and identification of RAG1 as a direct target","pmids":["39454110"],"is_preprint":false},{"year":2024,"finding":"In neuroblastoma, a super-enhancer driven by master TFs MYCN, MEIS2, and HAND2 activates IRF2BP2 expression. AP-1 family members shape chromatin accessibility to expose IRF2BP2 binding sites, and AP-1 and IRF2BP2 collaboratively stimulate expression of the NB susceptibility gene ALK to maintain the highly proliferative NB phenotype.","method":"ChIP-seq, ATAC-seq, transcriptome sequencing, loss-of-function experiments in NB cells, in vivo experiments","journal":"Neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and transcriptome sequencing with loss-of-function, single lab","pmids":["38864832"],"is_preprint":false},{"year":2025,"finding":"IRF2BP2 functions as a transcriptional repressor of adipocyte lipolysis by directly repressing lipolysis-related genes including LIPE (hormone-sensitive lipase). Adipocyte-selective deletion of Irf2bp2 in mice increased Lipe expression and free fatty acid levels, resulting in adipose tissue inflammation and glucose intolerance.","method":"ChIP-seq, RNA-seq, adipocyte-specific KO mice, primary human adipocyte deletion and overexpression, free fatty acid measurement","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP-seq demonstrating direct gene repression, RNA-seq, and adipocyte-specific KO mice with metabolic phenotype, multiple orthogonal methods","pmids":["39752494"],"is_preprint":false},{"year":2025,"finding":"In ven/aza-resistant AML, MCL1 binds IRF2BP2 (identified by co-IP of MCL1 coupled with mass spectrometry), resulting in cytoplasmic sequestration of IRF2BP2 and loss of its transcriptional repression. This de-represses ACSL1 (a rate-limiting enzyme for fatty acid oxidation), promoting ven/aza resistance in leukemic stem cells.","method":"Co-immunoprecipitation of MCL1 + mass spectrometry, subcellular fractionation, ACSL1 inhibition functional assays, gene expression in LSCs","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP/MS identifying MCL1 interaction, fractionation showing cytoplasmic localization, functional ACSL1 inhibition; preprint, not yet peer-reviewed","pmids":["40475530"],"is_preprint":true},{"year":2025,"finding":"IRF2BP2 cooperates with TRIM28 and DNMT1 to epigenetically silence transposable elements (particularly HERV-K/LTR5_Hs) in AML. Loss of IRF2BP2 induced differentiation and apoptosis linked to TE transcriptional activation; CRISPR activation of HERV-K recapitulated IRF2BP2 loss phenotypes, and targeted re-silencing of HERV-K partially rescued these effects.","method":"Single-cell Perturb-seq screen, CRISPR activation, ChIP/chromatin analyses for TRIM28/DNMT1 co-occupancy, rescue experiments","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Perturb-seq with mechanistic follow-up (CRISPR activation and re-silencing rescue), but preprint only","pmids":["bio_10.1101_2025.11.12.688028"],"is_preprint":true},{"year":2026,"finding":"An IRF2BP2::JAK2 fusion protein confers cytokine-independent growth in Ba/F3 cells, localizes to the cytoplasm, and drives constitutive JAK-STAT signaling. Both type I (ruxolitinib) and type II (CHZ868) JAK inhibitors potently inhibit the fusion.","method":"CRISPR-Cas9 engineering of Irf2bp2::Jak2 in Ba/F3 cells, cytokine-independent growth assay, subcellular localization, JAK inhibitor treatment","journal":"Genes, chromosomes & cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional modeling in Ba/F3 with cytokine-independence, localization, and inhibitor sensitivity; single study","pmids":["41711169"],"is_preprint":false},{"year":2024,"finding":"Variants in the C-terminal RING finger domain of IRF2BP2 caused irregular aggregate formation and cytoplasmic distribution rather than the expected nuclear localization, and impaired nuclear translocation of IRF2 and NFκB1 (p50), as shown in HEK293 cells expressing EGFP-fused mutants.","method":"Confocal fluorescence microscopy, immunoblotting, overexpression of EGFP-fused mutants, luciferase reporter for NFκB1","journal":"Clinical immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — fluorescence microscopy and western blotting of mutants, single lab, patient-derived variant context","pmids":["39059757"],"is_preprint":false},{"year":2036,"finding":"IRF2BP2 patient-derived mutant constructs showed impaired repression of NFAT activation compared to wild-type, as demonstrated by NFAT luciferase reporter assay in Jurkat cells. Mutant IRF2BP2 constructs also showed higher TNF-α transcript levels compared to wild-type IRF2BP2.","method":"NFAT luciferase reporter assay in Jurkat cells, quantitative cDNA determination","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay with patient-derived mutant constructs, functional validation in cell line, single lab","pmids":["40090425"],"is_preprint":false},{"year":2023,"finding":"IRF2BP2 promotes lymph node metastasis in oral squamous cell carcinoma by enhancing mitochondrial fission through contributing to Drp1 S616 phosphorylation and mitochondrial localization, which upregulates CPT1A expression and fatty acid oxidation. CPT1A overexpression rescued invasion in IRF2BP2-silenced cells.","method":"Confocal microscopy, transmission electron microscopy, immunofluorescence, western blot for Drp1 phosphorylation, CPT1A rescue experiment, in vivo xenograft model","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple imaging methods, epistasis via CPT1A rescue, in vivo validation; single lab","pmids":["37737489"],"is_preprint":false},{"year":2023,"finding":"Agmatine binds directly to IRF2BP2 (identified by protein microarray). This competitive binding releases IRF2, allowing free IRF2 to translocate to the BV2 microglia nucleus and activate KLF4 transcription, increasing CD206-positive (M2) microglial polarization.","method":"Protein microarray, immunofluorescence/nuclear translocation assay, flow cytometry for CD206","journal":"Inflammation research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — protein microarray binding and nuclear translocation readout, single lab, no direct biochemical binding confirmation beyond array","pmids":["37314519"],"is_preprint":false}],"current_model":"IRF2BP2 is a nuclear transcriptional co-regulator (capable of both co-repression and co-activation) that interacts with diverse partners—including IRF2, VGLL4, ZBTB16, NFAT1, MEF2C, HNF4α, GR, NF-κB, ATF7/JDP2, TRIM28, and DNMT1—via its RING finger domain (which recognizes a conserved RxSVI motif), to control gene programs governing macrophage/microglial inflammation, VEGFA and KLF2 expression, cardiac hypertrophy, hepatic lipid metabolism, adipocyte lipolysis, hematopoietic differentiation, and cancer cell survival; its cytoplasmic sequestration (e.g., by MCL1 in drug-resistant AML) abrogates its transcriptional repressor function, while loss-of-function mutations in humans cause immunodeficiency with impaired B-cell maturation and dysregulated NFAT/STAT signaling."},"narrative":{"mechanistic_narrative":"IRF2BP2 is a nuclear transcriptional co-regulator that controls gene programs governing inflammation, lipid metabolism, hematopoietic differentiation, and cancer cell survival, generally acting as a co-repressor but also as a context-dependent co-activator [PMID:20702774, PMID:38801077, PMID:39752494]. It engages transcription factor partners through a C-terminal RING finger domain that recognizes a conserved RxSVI motif present in IRF2, VGLL4, and ZBTB16, with structural and biochemical data showing the motif forms a short loop and β-strand that docks into the RING domain [PMID:39616187]. Through these interactions IRF2BP2 directly represses target genes: it binds and represses the ATF3 promoter in hepatocytes to protect against high-fat-diet steatosis and insulin resistance [PMID:31529495], represses LIPE and other lipolysis genes in adipocytes to restrain free fatty acid release and adipose inflammation [PMID:39752494], and acts as an HNF4α co-repressor in a manner dependent on its E3 ubiquitin ligase activity to restrain gluconeogenic genes [PMID:35609419]. In macrophages and microglia IRF2BP2 is required for MEF2-dependent activation of KLF2, driving anti-inflammatory and cholesterol-efflux programs whose loss worsens atherosclerosis and stroke outcome [PMID:26195219, PMID:28769762], and the same IRF2BP2/KLF2 axis governs osteoclast versus osteoblast differentiation [PMID:31186082]. It restrains hypertrophic and immune transcription by competing with MEF2C for the NFAT1 transactivation domain in cardiomyocytes and by binding NFAT1 to limit inflammatory signaling [PMID:28716987, PMID:33052070]. In the nucleus IRF2BP2 is recruited to chromatin by the ATF7/JDP2 AP-1 dimer to counteract gene activation [PMID:38801077], cooperates with TRIM28 and DNMT1 to silence HERV-K transposable elements in AML [PMID:bio_10.1101_2025.11.12.688028], and supports leukemia and tumor proliferation, being driven by super-enhancers and cooperating with master transcription factors to regulate targets such as RAG1 in T-ALL and ALK in neuroblastoma [PMID:39454110, PMID:38864832]. Loss-of-function and RING-domain mutations in humans cause an immunodeficiency with impaired B-cell/plasmablast maturation, defective repression of NFAT and STAT1, and aberrant cytoplasmic mislocalization and aggregation of the protein [PMID:27016798, PMID:34451894, PMID:39059757, PMID:40090425].","teleology":[{"year":2008,"claim":"Established the first functional context for IRF2BP2 by showing it is a p53 target that dampens the apoptotic response, framing it as a transcriptional modulator of stress programs.","evidence":"Reporter assays, siRNA knockdown, overexpression, and apoptosis assays in human cells","pmids":["19042971"],"confidence":"High","gaps":["Did not define direct DNA-binding or repressive mechanism at p53 target promoters","No partner protein identified"]},{"year":2010,"claim":"Identified IRF2BP2 as a TEAD4/VGLL4 complex component that activates VEGFA, demonstrating it can act as a co-activator within a defined transcription factor complex.","evidence":"Yeast 2-hybrid, reciprocal co-IP, mammalian 2-hybrid, and knockdown with VEGFA readout in C2C12 cells","pmids":["20702774"],"confidence":"High","gaps":["Mechanism of VEGFA activation not resolved at chromatin level","Did not establish whether activation versus repression is partner-determined"]},{"year":2015,"claim":"Defined an IRF2BP2/MEF2/KLF2 axis controlling macrophage anti-inflammatory and cholesterol-efflux programs, linking IRF2BP2 to atherosclerosis in vivo.","evidence":"Macrophage-specific conditional KO mice, promoter assays, and KLF2 rescue with cholesterol efflux readout","pmids":["26195219"],"confidence":"High","gaps":["Whether IRF2BP2 acts as activator or repressor at the KLF2 promoter not fully resolved","Direct chromatin occupancy not shown"]},{"year":2016,"claim":"Extended IRF2BP2 function to adaptive immunity by showing it restrains CD4 T-cell activation and to humans by linking a heterozygous mutation to CVID with impaired plasmablast formation.","evidence":"Retroviral transduction of primary CD4 T and B cells, flow cytometry, in vivo transfer, and exome sequencing of a CVID family","pmids":["27286791","27016798"],"confidence":"Medium","gaps":["Direct target genes in T/B cells not identified","Mechanism connecting mutation to plasmablast defect undefined"]},{"year":2017,"claim":"Revealed a competitive co-repression mechanism in which IRF2BP2 binds the NFAT1 transactivation domain to displace MEF2C and limit hypertrophic transcription, validated by genetic epistasis.","evidence":"Cardiomyocyte-specific KO and transgenic mice with aortic banding, reciprocal co-IP, NFAT1 blockade rescue","pmids":["28716987"],"confidence":"High","gaps":["Structural basis of NFAT1/MEF2C competition not resolved","Did not address whether other partners use the same competitive mechanism"]},{"year":2017,"claim":"Showed IRF2BP2 controls macrophage/microglial inflammatory polarization and IFNβ responses, connecting it to stroke injury outcomes.","evidence":"Conditional macrophage/microglia KO mice, photothrombotic stroke model, cytokine and IFNβ epistasis assays","pmids":["28769762"],"confidence":"High","gaps":["Direct transcriptional targets in microglia not mapped","Relationship to the KLF2 axis in this context not formalized"]},{"year":2019,"claim":"Established IRF2BP2 as a direct hepatic transcriptional repressor of ATF3 and a regulator of metabolic homeostasis, and extended the KLF2 axis to bone cell differentiation.","evidence":"Hepatocyte-specific KO/overexpression mice with ChIP-seq, luciferase and ATF3 rescue; osteoclast/osteoblast differentiation with KLF2 rescue","pmids":["31529495","31186082"],"confidence":"High","gaps":["Cofactors mediating ATF3 promoter repression not identified","Whether RING/E3 activity is required for ATF3 repression not tested"]},{"year":2019,"claim":"Connected IRF2BP2 to nuclear receptor and stress signaling by mapping glucocorticoid-dependent chromatin binding co-occurring with GR, and to erythropoiesis via VGLL4 sequestration that releases alas2 repression.","evidence":"ChIP-seq/RNA-seq with siRNA depletion in A549/HEK293 cells; CRISPR vgll4b zebrafish with irf2bp2-depletion rescue and TDU1/RING domain mapping","pmids":["31145973","31539803"],"confidence":"Medium","gaps":["Whether IRF2BP2 directly contacts GR not established","Domain-level data did not yet define the partner-binding motif"]},{"year":2020,"claim":"Demonstrated IRF2BP2 acts as a ubiquitin-ligase-dependent HNF4α co-repressor and confirmed NFAT1 binding as a node modulated by miRNA and small molecules.","evidence":"Specialized proteomic interaction detection, reporter assays with E3-ligase mutant, CRISPR KO HepG2; co-IP, miR-155 reporter assay, shRNA in mice","pmids":["35609419","33052070"],"confidence":"Medium","gaps":["HNF4α interaction undetectable by conventional IP, leaving stoichiometry uncertain","Ubiquitination substrate of the E3 activity not identified"]},{"year":2021,"claim":"Linked human IRF2BP2 deficiency to dysregulated STAT signaling by showing a deletion variant fails to suppress STAT1, with patients showing constitutive STAT1/STAT5 activation.","evidence":"Luciferase reporter, phospho-STAT flow cytometry, NanoString in patient samples","pmids":["34451894"],"confidence":"Medium","gaps":["Direct mechanism by which IRF2BP2 represses STAT1 transcription not defined","Single family/lab"]},{"year":2024,"claim":"Provided the structural and biochemical basis for IRF2BP2 partner selection, defining RING-domain recognition of a conserved RxSVI motif shared by IRF2, VGLL4, and ZBTB16, and a role in megakaryocytic differentiation.","evidence":"Motif discovery, biochemical binding assays, structural determination, and differentiation assays","pmids":["39616187"],"confidence":"High","gaps":["Whether all functional partners use the RxSVI motif not exhaustively tested","How motif binding dictates repression versus activation unresolved"]},{"year":2024,"claim":"Established IRF2BP2 as a chromatin co-repressor of AP-1 (ATF7/JDP2) and an oncogenic dependency in leukemia driven by super-enhancers cooperating with master transcription factors.","evidence":"Co-IP and chromatin recruitment assays with RNA-seq in AML; CUT&Tag, IP, conditional KO mice in T-ALL targeting RAG1; ChIP/ATAC-seq with loss-of-function in neuroblastoma targeting ALK","pmids":["38801077","39454110","38864832"],"confidence":"High","gaps":["How IRF2BP2 switches between repressing AP-1 and co-activating master TF targets not reconciled","Direct versus indirect effects on MYC/E2F pathways not separated"]},{"year":2024,"claim":"Connected human RING-domain mutations to a cell-biological defect: aberrant cytoplasmic aggregation and impaired nuclear translocation of IRF2 and NF-κB1.","evidence":"Confocal microscopy and immunoblotting of EGFP-fused mutants with NF-κB1 reporter in HEK293","pmids":["39059757"],"confidence":"Medium","gaps":["Whether aggregation is a direct cause of partner mislocalization or a downstream consequence unclear","Overexpression system may not reflect endogenous behavior"]},{"year":2025,"claim":"Defined IRF2BP2 as a direct transcriptional repressor of adipocyte lipolysis genes including LIPE, establishing its role in systemic metabolic and inflammatory homeostasis.","evidence":"ChIP-seq, RNA-seq, adipocyte-specific KO mice, primary human adipocyte deletion/overexpression with FFA measurement","pmids":["39752494"],"confidence":"High","gaps":["Cofactors required for LIPE promoter repression not identified","Relationship to hepatic ATF3 repression mechanism not compared"]},{"year":2025,"claim":"Revealed regulation of IRF2BP2 by spatial sequestration and an epigenetic silencing partnership: MCL1 traps it in the cytoplasm to de-repress fatty-acid-oxidation genes in drug-resistant AML, and it cooperates with TRIM28/DNMT1 to silence transposable elements.","evidence":"Co-IP/MS, subcellular fractionation, ACSL1 functional assays (preprint); Perturb-seq, CRISPR activation/re-silencing of HERV-K, TRIM28/DNMT1 co-occupancy (preprint)","pmids":["40475530","bio_10.1101_2025.11.12.688028"],"confidence":"Medium","gaps":["Preprint findings not yet peer-reviewed","Whether cytoplasmic sequestration is reversible/regulated physiologically unknown"]},{"year":2026,"claim":"Showed an IRF2BP2::JAK2 fusion is an oncogenic, cytoplasmically localized driver of constitutive JAK-STAT signaling that is targetable by JAK inhibitors.","evidence":"CRISPR-engineered Ba/F3 cytokine-independence, localization, and JAK-inhibitor sensitivity assays","pmids":["41711169"],"confidence":"Medium","gaps":["Contribution of the IRF2BP2 portion to fusion activity not dissected","Single experimental system"]},{"year":null,"claim":"It remains unresolved how IRF2BP2 chooses between transcriptional repression and activation at different partners and loci, and what substrate its E3 ubiquitin ligase activity acts upon.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No identified ubiquitination substrate despite an E3-activity-dependent repression function","No unified model linking RxSVI-motif binding to activator versus repressor outcome","Regulation of nuclear/cytoplasmic partitioning under physiological conditions undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3,10,13,15,18]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[13]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[10,18]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,14,15]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,10,18,22]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[19,21,22]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,10,15,18]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,6,12,23]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[10,13,18]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[15,20]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[16,17,19,21]}],"complexes":["TEAD4/VGLL4 transcription factor complex","ATF7/JDP2 AP-1 chromatin complex","TRIM28/DNMT1 silencing complex"],"partners":["VGLL4","NFAT1","MEF2C","HNF4A","IRF2","ZBTB16","TRIM28","MCL1"],"other_free_text":[]}},"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; 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the TEAD4/VGLL4 transcription factor complex via yeast 2-hybrid screen from a human heart cDNA library, confirmed in vivo by co-immunoprecipitation and mammalian 2-hybrid assays. Co-expression of IRF2BP2 with TEAD4/VGLL4 or TEAD1 potently activated VEGFA expression, while knockdown reduced VEGFA expression in C2C12 muscle cells.\",\n      \"method\": \"Yeast 2-hybrid, co-immunoprecipitation, mammalian 2-hybrid, knockdown with gene expression readout\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, mammalian 2-hybrid, and knockdown with functional readout in single study with multiple orthogonal methods\",\n      \"pmids\": [\"20702774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IRF2BP2 is a direct transcriptional target of p53; its upregulation after actinomycin D treatment is p53-dependent. Overexpressed IRF2BP2 impedes p53-mediated transactivation of p21 and Bax genes, diminishes apoptosis after doxorubicin treatment, and its knockdown leads to upregulation of p21 and faster apoptosis induction.\",\n      \"method\": \"Reporter assays, loss-of-function (siRNA knockdown), gain-of-function (overexpression), cell viability/apoptosis assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, KD, OE, apoptosis assays) in a single focused study\",\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, as shown by promoter studies. IRF2BP2-deficient macrophages have markedly reduced KLF2 expression, impaired ABCA1 activation in response to cholesterol loading, and worsened atherosclerosis; restoring KLF2 in IRF2BP2-deficient macrophages rescued anti-inflammatory gene activation and cholesterol efflux.\",\n      \"method\": \"Macrophage-specific conditional knockout mice, promoter assays, rescue experiments with KLF2 restoration, cholesterol efflux assays\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO in two mouse atherosclerosis models, promoter studies, and rescue experiments with orthogonal readouts\",\n      \"pmids\": [\"26195219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IRF2BP2 directly interacts with the C-terminal transactivation domain of NFAT1 by competing with MEF2C, disturbing their transcriptional synergism and impeding NFAT1-transactivated hypertrophic transcriptome in cardiomyocytes. Cardiomyocyte-specific Irf2bp2 knockout exacerbated cardiac hypertrophy, while Irf2bp2 transgenic overexpression was protective; the effect of Irf2bp2 deficiency was rescued by NFAT1 blockage.\",\n      \"method\": \"Cardiomyocyte-specific KO and transgenic mouse models, co-immunoprecipitation of IRF2BP2-NFAT1 interaction, aortic banding and angiotensin II infusion models\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (NFAT1 blockage rescues KO phenotype), reciprocal interaction assay, and two in vivo KO/transgenic models\",\n      \"pmids\": [\"28716987\"],\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, and proliferative capacity following TCR stimulation; IRF2BP2-overexpressing cells showed impaired in vivo expansion capacity. IRF2BP2 expression was decreased in CD4 T cells upon activation.\",\n      \"method\": \"Retroviral transduction of primary CD4 T cells, flow cytometry, in vivo adoptive transfer\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function in primary cells with in vivo validation, but single lab and no direct target gene mechanism identified\",\n      \"pmids\": [\"27286791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A heterozygous IRF2BP2 mutation (c.1652G>A:p.[S551N]) was identified in a family with CVID. Transduction of mutant IRF2BP2 into control human B cells decreased production of plasmablasts in vitro, demonstrating a role for IRF2BP2 in B-cell differentiation.\",\n      \"method\": \"Whole-exome sequencing, retroviral transduction into human B cells, in vitro plasmablast differentiation assay, protein immunoblots\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional transduction experiment in primary human B cells, supported by clinical variant, single lab\",\n      \"pmids\": [\"27016798\"],\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 macrophages/microglia lost the anti-inflammatory effect of IFNβ, and mice lacking IRF2BP2 in macrophages/microglia showed larger infarctions and worse functional outcomes after photothrombotic stroke.\",\n      \"method\": \"Conditional macrophage/microglia-specific KO mice, photothrombotic stroke model, cytokine measurements, IFNβ treatment\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multiple in vitro and in vivo readouts, IFNβ epistasis experiment, consistent with prior macrophage data\",\n      \"pmids\": [\"28769762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IRF2BP2 overexpression suppressed osteoclast differentiation and enhanced osteoblast differentiation; these effects were reversed by KLF2 knockdown, establishing an IRF2BP2/KLF2 axis in bone cell differentiation. KLF2 overexpression inhibited osteoclast differentiation by downregulating c-Fos, NFATc1, and TRAP.\",\n      \"method\": \"Overexpression, siRNA knockdown, osteoclast/osteoblast differentiation assays\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — epistasis via KLF2 rescue experiment, but gain/loss of function only, single lab\",\n      \"pmids\": [\"31186082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IRF2BP2 modulates glucocorticoid (GC) receptor (GR) and NF-κB signaling: GC changes chromatin binding of IRF2BP2, GC-induced IRF2BP2-binding sites co-occur with GR binding sites and associate with GC-induced genes. Depletion of IRF2BP2 modulates GC-regulated gene transcription and alters responses to both GC and TNFα.\",\n      \"method\": \"ChIP-seq (chromatin immunoprecipitation sequencing), siRNA depletion, RNA-seq in A549 and HEK293 cells\",\n      \"journal\": \"The Journal of steroid biochemistry and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and RNA-seq with KD, two orthogonal methods, single lab\",\n      \"pmids\": [\"31145973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In zebrafish, VGLL4 sequesters IRF2BP2 via their respective TDU1 and RING finger domains, thereby preventing IRF2BP2 from repressing alas2 expression and heme biosynthesis during erythroid terminal differentiation. irf2bp2 depletion rescued the impaired erythroid phenotype of vgll4b mutant zebrafish.\",\n      \"method\": \"CRISPR/Cas9 vgll4b mutant zebrafish, genetic rescue by irf2bp2 depletion, domain mapping (TDU1/RING finger)\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in zebrafish with domain-level interaction data, single lab\",\n      \"pmids\": [\"31539803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IRF2BP2 directly represses ATF3 gene expression in hepatocytes by binding to the ATF3 promoter region, as demonstrated by ChIP-seq and luciferase assay. Hepatocyte-specific Irf2bp2 knockout exacerbated high-fat diet-induced hepatic steatosis, insulin resistance and inflammation, while hepatic overexpression was protective; ATF3 knockdown relieved the effects of IRF2BP2 knockout.\",\n      \"method\": \"Hepatocyte-specific KO and overexpression mouse models, ChIP-seq, luciferase assay, digital gene expression analysis, ATF3 siRNA rescue\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP-seq confirming direct promoter binding, luciferase validation, genetic epistasis via ATF3 KD rescue, in vivo KO and overexpression\",\n      \"pmids\": [\"31529495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IRF2BP2 binds to NFAT1, and this interaction is increased by the natural compound Oroxylin A. IRF2BP2 binding to NFAT1 was demonstrated by immunoprecipitation assay and is linked to regulation of inducible nitric oxide synthase and inflammatory signaling. miR-155-5p targets IRF2BP2 mRNA (validated by reporter assay), reducing IRF2BP2 levels.\",\n      \"method\": \"Immunoprecipitation assay, miRNA array, luciferase reporter assay, shRNA injection in mice\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — immunoprecipitation of IRF2BP2-NFAT1 interaction and reporter assay validation of miR-155 targeting, but single lab\",\n      \"pmids\": [\"33052070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IRF2BP2 is required to attenuate STAT1 transcriptional activity; an IRF2BP2 deletion variant (c.625_665del) failed to suppress STAT1 transcription in a luciferase reporter system. Patients with this mutation showed overexpression and constitutive activation of STAT1, upregulated IFN-JAK-STAT signaling, and elevated STAT5 phosphorylation in CD4+ T cells.\",\n      \"method\": \"Luciferase reporter assay, flow cytometry for phospho-STAT quantification, NanoString gene expression, clinical patient samples\",\n      \"journal\": \"Pharmaceuticals\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay mechanistically links IRF2BP2 to STAT1 repression, supported by patient cell data, single lab\",\n      \"pmids\": [\"34451894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IRF2BP2 represses transcriptional activity of HNF4α and functions as a novel HNF4α co-repressor. The IRF2BP2-HNF4α interaction was detectable only by novel proteomic techniques (not conventional immunoprecipitation). IRF2BP2 repressed HNF4α transcriptional activity in a manner dependent on its E3 ubiquitin ligase activity, and IRF2BP2 gene deficiency in HepG2 cells induced gluconeogenic genes.\",\n      \"method\": \"Novel proteomic interaction techniques, reporter assay, CRISPR KO of IRF2BP2 in HepG2 cells, gluconeogenic gene expression measurement\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay with E3 ligase mutant and KO cell line; interaction only detectable by specialized proteomics, not conventional IP\",\n      \"pmids\": [\"35609419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The RING domain of IRF2BP2 binds to a conserved RxSVI motif present in interacting partners IRF2, VGLL4, and ZBTB16. Biochemical and structural data show that motif-containing peptides form a short loop with a short β-strand facilitating RING domain recognition. IRF2BP2 plays a regulatory role in megakaryocytic differentiation through its interaction with ZBTB16.\",\n      \"method\": \"Motif discovery, biochemical binding assays, structural determination (crystal/NMR), cell biological assays of megakaryocytic differentiation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural data combined with biochemical binding assays and cell biological functional validation in a single rigorous study\",\n      \"pmids\": [\"39616187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IRF2BP2 interacts with the AP-1 heterodimer ATF7/JDP2 and is recruited to chromatin by this dimer, where it counteracts ATF7/JDP2 gene-activating function. Loss of IRF2BP2 causes overactivation of inflammatory pathways in AML cells, resulting in strongly reduced proliferation.\",\n      \"method\": \"Co-immunoprecipitation, chromatin recruitment assays, IRF2BP2 loss-of-function in AML cells with RNA-seq\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, chromatin recruitment, and transcriptomic readout with multiple orthogonal methods in a single study\",\n      \"pmids\": [\"38801077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IRF2BP2 is driven by a super-enhancer in T-ALL regulated by master TFs (ERG, ELF1, ETS1). CUT&Tag and immunoprecipitation show IRF2BP2 cooperates with T-ALL master TFs to target the enhancer of RAG1 and modulate its expression. IRF2BP2 is crucial for T-ALL cell growth and survival in vitro and in vivo, and loss affects MYC and E2F pathways.\",\n      \"method\": \"CUT&Tag, immunoprecipitation, conditional KO mice (hematopoietic-specific), in vitro and in vivo T-ALL models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CUT&Tag, IP, conditional KO mice with both in vitro and in vivo validation, and identification of RAG1 as a direct target\",\n      \"pmids\": [\"39454110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In neuroblastoma, a super-enhancer driven by master TFs MYCN, MEIS2, and HAND2 activates IRF2BP2 expression. AP-1 family members shape chromatin accessibility to expose IRF2BP2 binding sites, and AP-1 and IRF2BP2 collaboratively stimulate expression of the NB susceptibility gene ALK to maintain the highly proliferative NB phenotype.\",\n      \"method\": \"ChIP-seq, ATAC-seq, transcriptome sequencing, loss-of-function experiments in NB cells, in vivo experiments\",\n      \"journal\": \"Neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and transcriptome sequencing with loss-of-function, single lab\",\n      \"pmids\": [\"38864832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IRF2BP2 functions as a transcriptional repressor of adipocyte lipolysis by directly repressing lipolysis-related genes including LIPE (hormone-sensitive lipase). Adipocyte-selective deletion of Irf2bp2 in mice increased Lipe expression and free fatty acid levels, resulting in adipose tissue inflammation and glucose intolerance.\",\n      \"method\": \"ChIP-seq, RNA-seq, adipocyte-specific KO mice, primary human adipocyte deletion and overexpression, free fatty acid measurement\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP-seq demonstrating direct gene repression, RNA-seq, and adipocyte-specific KO mice with metabolic phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"39752494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In ven/aza-resistant AML, MCL1 binds IRF2BP2 (identified by co-IP of MCL1 coupled with mass spectrometry), resulting in cytoplasmic sequestration of IRF2BP2 and loss of its transcriptional repression. This de-represses ACSL1 (a rate-limiting enzyme for fatty acid oxidation), promoting ven/aza resistance in leukemic stem cells.\",\n      \"method\": \"Co-immunoprecipitation of MCL1 + mass spectrometry, subcellular fractionation, ACSL1 inhibition functional assays, gene expression in LSCs\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP/MS identifying MCL1 interaction, fractionation showing cytoplasmic localization, functional ACSL1 inhibition; preprint, not yet peer-reviewed\",\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 (particularly HERV-K/LTR5_Hs) in AML. Loss of IRF2BP2 induced differentiation and apoptosis linked to TE transcriptional activation; CRISPR activation of HERV-K recapitulated IRF2BP2 loss phenotypes, and targeted re-silencing of HERV-K partially rescued these effects.\",\n      \"method\": \"Single-cell Perturb-seq screen, CRISPR activation, ChIP/chromatin analyses for TRIM28/DNMT1 co-occupancy, rescue experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Perturb-seq with mechanistic follow-up (CRISPR activation and re-silencing rescue), but preprint only\",\n      \"pmids\": [\"bio_10.1101_2025.11.12.688028\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"An IRF2BP2::JAK2 fusion protein confers cytokine-independent growth in Ba/F3 cells, localizes to the cytoplasm, and drives constitutive JAK-STAT signaling. Both type I (ruxolitinib) and type II (CHZ868) JAK inhibitors potently inhibit the fusion.\",\n      \"method\": \"CRISPR-Cas9 engineering of Irf2bp2::Jak2 in Ba/F3 cells, cytokine-independent growth assay, subcellular localization, JAK inhibitor treatment\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional modeling in Ba/F3 with cytokine-independence, localization, and inhibitor sensitivity; single study\",\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 cytoplasmic distribution rather than the expected nuclear localization, and impaired nuclear translocation of IRF2 and NFκB1 (p50), as shown in HEK293 cells expressing EGFP-fused mutants.\",\n      \"method\": \"Confocal fluorescence microscopy, immunoblotting, overexpression of EGFP-fused mutants, luciferase reporter for NFκB1\",\n      \"journal\": \"Clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — fluorescence microscopy and western blotting of mutants, single lab, patient-derived variant context\",\n      \"pmids\": [\"39059757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2036,\n      \"finding\": \"IRF2BP2 patient-derived mutant constructs showed impaired repression of NFAT activation compared to wild-type, as demonstrated by NFAT luciferase reporter assay in Jurkat cells. Mutant IRF2BP2 constructs also showed higher TNF-α transcript levels compared to wild-type IRF2BP2.\",\n      \"method\": \"NFAT luciferase reporter assay in Jurkat cells, quantitative cDNA determination\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay with patient-derived mutant constructs, functional validation in cell line, single lab\",\n      \"pmids\": [\"40090425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IRF2BP2 promotes lymph node metastasis in oral squamous cell carcinoma by enhancing mitochondrial fission through contributing to Drp1 S616 phosphorylation and mitochondrial localization, which upregulates CPT1A expression and fatty acid oxidation. CPT1A overexpression rescued invasion in IRF2BP2-silenced cells.\",\n      \"method\": \"Confocal microscopy, transmission electron microscopy, immunofluorescence, western blot for Drp1 phosphorylation, CPT1A rescue experiment, in vivo xenograft model\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple imaging methods, epistasis via CPT1A rescue, in vivo validation; single lab\",\n      \"pmids\": [\"37737489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Agmatine binds directly to IRF2BP2 (identified by protein microarray). This competitive binding releases IRF2, allowing free IRF2 to translocate to the BV2 microglia nucleus and activate KLF4 transcription, increasing CD206-positive (M2) microglial polarization.\",\n      \"method\": \"Protein microarray, immunofluorescence/nuclear translocation assay, flow cytometry for CD206\",\n      \"journal\": \"Inflammation research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — protein microarray binding and nuclear translocation readout, single lab, no direct biochemical binding confirmation beyond array\",\n      \"pmids\": [\"37314519\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IRF2BP2 is a nuclear transcriptional co-regulator (capable of both co-repression and co-activation) that interacts with diverse partners—including IRF2, VGLL4, ZBTB16, NFAT1, MEF2C, HNF4α, GR, NF-κB, ATF7/JDP2, TRIM28, and DNMT1—via its RING finger domain (which recognizes a conserved RxSVI motif), to control gene programs governing macrophage/microglial inflammation, VEGFA and KLF2 expression, cardiac hypertrophy, hepatic lipid metabolism, adipocyte lipolysis, hematopoietic differentiation, and cancer cell survival; its cytoplasmic sequestration (e.g., by MCL1 in drug-resistant AML) abrogates its transcriptional repressor function, while loss-of-function mutations in humans cause immunodeficiency with impaired B-cell maturation and dysregulated NFAT/STAT signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IRF2BP2 is a nuclear transcriptional co-regulator that controls gene programs governing inflammation, lipid metabolism, hematopoietic differentiation, and cancer cell survival, generally acting as a co-repressor but also as a context-dependent co-activator [#0, #15, #18]. It engages transcription factor partners through a C-terminal RING finger domain that recognizes a conserved RxSVI motif present in IRF2, VGLL4, and ZBTB16, with structural and biochemical data showing the motif forms a short loop and β-strand that docks into the RING domain [#14]. Through these interactions IRF2BP2 directly represses target genes: it binds and represses the ATF3 promoter in hepatocytes to protect against high-fat-diet steatosis and insulin resistance [#10], represses LIPE and other lipolysis genes in adipocytes to restrain free fatty acid release and adipose inflammation [#18], and acts as an HNF4α co-repressor in a manner dependent on its E3 ubiquitin ligase activity to restrain gluconeogenic genes [#13]. In macrophages and microglia IRF2BP2 is required for MEF2-dependent activation of KLF2, driving anti-inflammatory and cholesterol-efflux programs whose loss worsens atherosclerosis and stroke outcome [#2, #6], and the same IRF2BP2/KLF2 axis governs osteoclast versus osteoblast differentiation [#7]. It restrains hypertrophic and immune transcription by competing with MEF2C for the NFAT1 transactivation domain in cardiomyocytes and by binding NFAT1 to limit inflammatory signaling [#3, #11]. In the nucleus IRF2BP2 is recruited to chromatin by the ATF7/JDP2 AP-1 dimer to counteract gene activation [#15], cooperates with TRIM28 and DNMT1 to silence HERV-K transposable elements in AML [#20], and supports leukemia and tumor proliferation, being driven by super-enhancers and cooperating with master transcription factors to regulate targets such as RAG1 in T-ALL and ALK in neuroblastoma [#16, #17]. Loss-of-function and RING-domain mutations in humans cause an immunodeficiency with impaired B-cell/plasmablast maturation, defective repression of NFAT and STAT1, and aberrant cytoplasmic mislocalization and aggregation of the protein [#5, #12, #22, #23].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established the first functional context for IRF2BP2 by showing it is a p53 target that dampens the apoptotic response, framing it as a transcriptional modulator of stress programs.\",\n      \"evidence\": \"Reporter assays, siRNA knockdown, overexpression, and apoptosis assays in human cells\",\n      \"pmids\": [\"19042971\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define direct DNA-binding or repressive mechanism at p53 target promoters\", \"No partner protein identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified IRF2BP2 as a TEAD4/VGLL4 complex component that activates VEGFA, demonstrating it can act as a co-activator within a defined transcription factor complex.\",\n      \"evidence\": \"Yeast 2-hybrid, reciprocal co-IP, mammalian 2-hybrid, and knockdown with VEGFA readout in C2C12 cells\",\n      \"pmids\": [\"20702774\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of VEGFA activation not resolved at chromatin level\", \"Did not establish whether activation versus repression is partner-determined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined an IRF2BP2/MEF2/KLF2 axis controlling macrophage anti-inflammatory and cholesterol-efflux programs, linking IRF2BP2 to atherosclerosis in vivo.\",\n      \"evidence\": \"Macrophage-specific conditional KO mice, promoter assays, and KLF2 rescue with cholesterol efflux readout\",\n      \"pmids\": [\"26195219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IRF2BP2 acts as activator or repressor at the KLF2 promoter not fully resolved\", \"Direct chromatin occupancy not shown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended IRF2BP2 function to adaptive immunity by showing it restrains CD4 T-cell activation and to humans by linking a heterozygous mutation to CVID with impaired plasmablast formation.\",\n      \"evidence\": \"Retroviral transduction of primary CD4 T and B cells, flow cytometry, in vivo transfer, and exome sequencing of a CVID family\",\n      \"pmids\": [\"27286791\", \"27016798\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct target genes in T/B cells not identified\", \"Mechanism connecting mutation to plasmablast defect undefined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed a competitive co-repression mechanism in which IRF2BP2 binds the NFAT1 transactivation domain to displace MEF2C and limit hypertrophic transcription, validated by genetic epistasis.\",\n      \"evidence\": \"Cardiomyocyte-specific KO and transgenic mice with aortic banding, reciprocal co-IP, NFAT1 blockade rescue\",\n      \"pmids\": [\"28716987\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of NFAT1/MEF2C competition not resolved\", \"Did not address whether other partners use the same competitive mechanism\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed IRF2BP2 controls macrophage/microglial inflammatory polarization and IFNβ responses, connecting it to stroke injury outcomes.\",\n      \"evidence\": \"Conditional macrophage/microglia KO mice, photothrombotic stroke model, cytokine and IFNβ epistasis assays\",\n      \"pmids\": [\"28769762\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets in microglia not mapped\", \"Relationship to the KLF2 axis in this context not formalized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established IRF2BP2 as a direct hepatic transcriptional repressor of ATF3 and a regulator of metabolic homeostasis, and extended the KLF2 axis to bone cell differentiation.\",\n      \"evidence\": \"Hepatocyte-specific KO/overexpression mice with ChIP-seq, luciferase and ATF3 rescue; osteoclast/osteoblast differentiation with KLF2 rescue\",\n      \"pmids\": [\"31529495\", \"31186082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactors mediating ATF3 promoter repression not identified\", \"Whether RING/E3 activity is required for ATF3 repression not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected IRF2BP2 to nuclear receptor and stress signaling by mapping glucocorticoid-dependent chromatin binding co-occurring with GR, and to erythropoiesis via VGLL4 sequestration that releases alas2 repression.\",\n      \"evidence\": \"ChIP-seq/RNA-seq with siRNA depletion in A549/HEK293 cells; CRISPR vgll4b zebrafish with irf2bp2-depletion rescue and TDU1/RING domain mapping\",\n      \"pmids\": [\"31145973\", \"31539803\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IRF2BP2 directly contacts GR not established\", \"Domain-level data did not yet define the partner-binding motif\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated IRF2BP2 acts as a ubiquitin-ligase-dependent HNF4α co-repressor and confirmed NFAT1 binding as a node modulated by miRNA and small molecules.\",\n      \"evidence\": \"Specialized proteomic interaction detection, reporter assays with E3-ligase mutant, CRISPR KO HepG2; co-IP, miR-155 reporter assay, shRNA in mice\",\n      \"pmids\": [\"35609419\", \"33052070\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"HNF4α interaction undetectable by conventional IP, leaving stoichiometry uncertain\", \"Ubiquitination substrate of the E3 activity not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked human IRF2BP2 deficiency to dysregulated STAT signaling by showing a deletion variant fails to suppress STAT1, with patients showing constitutive STAT1/STAT5 activation.\",\n      \"evidence\": \"Luciferase reporter, phospho-STAT flow cytometry, NanoString in patient samples\",\n      \"pmids\": [\"34451894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism by which IRF2BP2 represses STAT1 transcription not defined\", \"Single family/lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided the structural and biochemical basis for IRF2BP2 partner selection, defining RING-domain recognition of a conserved RxSVI motif shared by IRF2, VGLL4, and ZBTB16, and a role in megakaryocytic differentiation.\",\n      \"evidence\": \"Motif discovery, biochemical binding assays, structural determination, and differentiation assays\",\n      \"pmids\": [\"39616187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether all functional partners use the RxSVI motif not exhaustively tested\", \"How motif binding dictates repression versus activation unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established IRF2BP2 as a chromatin co-repressor of AP-1 (ATF7/JDP2) and an oncogenic dependency in leukemia driven by super-enhancers cooperating with master transcription factors.\",\n      \"evidence\": \"Co-IP and chromatin recruitment assays with RNA-seq in AML; CUT&Tag, IP, conditional KO mice in T-ALL targeting RAG1; ChIP/ATAC-seq with loss-of-function in neuroblastoma targeting ALK\",\n      \"pmids\": [\"38801077\", \"39454110\", \"38864832\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How IRF2BP2 switches between repressing AP-1 and co-activating master TF targets not reconciled\", \"Direct versus indirect effects on MYC/E2F pathways not separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected human RING-domain mutations to a cell-biological defect: aberrant cytoplasmic aggregation and impaired nuclear translocation of IRF2 and NF-κB1.\",\n      \"evidence\": \"Confocal microscopy and immunoblotting of EGFP-fused mutants with NF-κB1 reporter in HEK293\",\n      \"pmids\": [\"39059757\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether aggregation is a direct cause of partner mislocalization or a downstream consequence unclear\", \"Overexpression system may not reflect endogenous behavior\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined IRF2BP2 as a direct transcriptional repressor of adipocyte lipolysis genes including LIPE, establishing its role in systemic metabolic and inflammatory homeostasis.\",\n      \"evidence\": \"ChIP-seq, RNA-seq, adipocyte-specific KO mice, primary human adipocyte deletion/overexpression with FFA measurement\",\n      \"pmids\": [\"39752494\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactors required for LIPE promoter repression not identified\", \"Relationship to hepatic ATF3 repression mechanism not compared\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed regulation of IRF2BP2 by spatial sequestration and an epigenetic silencing partnership: MCL1 traps it in the cytoplasm to de-repress fatty-acid-oxidation genes in drug-resistant AML, and it cooperates with TRIM28/DNMT1 to silence transposable elements.\",\n      \"evidence\": \"Co-IP/MS, subcellular fractionation, ACSL1 functional assays (preprint); Perturb-seq, CRISPR activation/re-silencing of HERV-K, TRIM28/DNMT1 co-occupancy (preprint)\",\n      \"pmids\": [\"40475530\", \"bio_10.1101_2025.11.12.688028\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint findings not yet peer-reviewed\", \"Whether cytoplasmic sequestration is reversible/regulated physiologically unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed an IRF2BP2::JAK2 fusion is an oncogenic, cytoplasmically localized driver of constitutive JAK-STAT signaling that is targetable by JAK inhibitors.\",\n      \"evidence\": \"CRISPR-engineered Ba/F3 cytokine-independence, localization, and JAK-inhibitor sensitivity assays\",\n      \"pmids\": [\"41711169\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Contribution of the IRF2BP2 portion to fusion activity not dissected\", \"Single experimental system\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how IRF2BP2 chooses between transcriptional repression and activation at different partners and loci, and what substrate its E3 ubiquitin ligase activity acts upon.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No identified ubiquitination substrate despite an E3-activity-dependent repression function\", \"No unified model linking RxSVI-motif binding to activator versus repressor outcome\", \"Regulation of nuclear/cytoplasmic partitioning under physiological conditions undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3, 10, 13, 15, 18]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [10, 18]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 14, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 10, 18, 22]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [19, 21, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 10, 15, 18]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 6, 12, 23]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [10, 13, 18]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [15, 20]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [16, 17, 19, 21]}\n    ],\n    \"complexes\": [\n      \"TEAD4/VGLL4 transcription factor complex\",\n      \"ATF7/JDP2 AP-1 chromatin complex\",\n      \"TRIM28/DNMT1 silencing complex\"\n    ],\n    \"partners\": [\n      \"VGLL4\",\n      \"NFAT1\",\n      \"MEF2C\",\n      \"HNF4A\",\n      \"IRF2\",\n      \"ZBTB16\",\n      \"TRIM28\",\n      \"MCL1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}