{"gene":"IRX1","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2015,"finding":"IRX1 promotes osteosarcoma metastasis by upregulating CXCL14/NF-κB signaling; experimental modulation of IRX1 in osteosarcoma cell lines altered migration, invasion, and resistance to anoikis in vitro, and lung metastasis in murine models, with effects mediated through CXCL14/NF-κB pathway activation.","method":"MeDIP-microarray screening, IRX1 overexpression/knockdown in cell lines, in vitro migration/invasion/anoikis assays, murine lung metastasis models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (gain- and loss-of-function, in vitro and in vivo), pathway mechanistically defined with specific downstream effector","pmids":["25822025"],"is_preprint":false},{"year":2010,"finding":"IRX1 functions as a tumor suppressor in gastric cancer; its expression is silenced by promoter hypermethylation (not mutation), and restoring IRX1 expression inhibits growth, invasion, and tumorigenesis. Direct IRX1 target genes identified by ChIP assay include BDKRB2, HIST2H2BE, and FGF7.","method":"5-Aza-dC treatment, IRX1 transfection, global microarray, real-time PCR, chromatin immunoprecipitation (ChIP), in vitro and in vivo tumorigenesis assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP confirmed direct target genes, multiple orthogonal functional assays, in vitro and in vivo validation","pmids":["20440264"],"is_preprint":false},{"year":2011,"finding":"IRX1 suppresses peritoneal spreading and pulmonary metastasis in gastric cancer via inhibition of angiogenesis and vasculogenic mimicry (VM), mechanistically through downregulation of its direct target BDKRB2 and its downstream effector PAK1; siRNA knockdown of BDKRB2 or PAK1 inhibited tube formation, proliferation, migration, and invasion.","method":"IRX1 transfection, siRNA knockdown of BDKRB2/PAK1, HUVEC angiogenesis assays, chick embryo assay, VM formation assay, in vivo murine metastasis models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic pathway (IRX1→BDKRB2→PAK1) validated by gene-specific RNAi and multiple functional readouts in vitro and in vivo","pmids":["21602894"],"is_preprint":false},{"year":2018,"finding":"PRMT5 acts as an upstream epigenetic repressor of IRX1 in gastric cancer by recruiting DNMT3A to the IRX1 promoter, increasing promoter methylation and silencing IRX1 expression; Co-IP confirmed PRMT5-DNMT3A interaction and ChIP confirmed DNMT3A recruitment to the IRX1 promoter.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), PRMT5 overexpression/knockdown, methylation analysis, in vitro and in vivo tumorigenicity assays","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reciprocal Co-IP and ChIP establish the PRMT5-DNMT3A-IRX1 promoter mechanism; functional rescue supports pathway placement","pmids":["29802960"],"is_preprint":false},{"year":2017,"finding":"Irx1 null mice are neonatal lethal due to pulmonary immaturity; Irx1 marks alveolar type II cells and is required for surfactant protein secretion. In dental development, Irx1 is expressed in outer enamel epithelium and mediates dental epithelial cell differentiation. Mechanistically, Irx1 regulates Foxj1 and Sox9 to control cell differentiation.","method":"Irx1 LacZ knock-in null mice, histology, LacZ lineage tracing, lung and dental phenotype analysis, target gene expression analysis (Foxj1, Sox9)","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function mouse model with specific cellular phenotype and identified downstream transcriptional targets, single lab","pmids":["28746823"],"is_preprint":false},{"year":2016,"finding":"IRX1 binds to the MLL-AF4 complex at target gene promoters and counteracts its promoter-activating function in t(4;11) leukemia cells; IRX1 also induces transcription of HOXB4 and EGR family members.","method":"ChIP at target gene promoters, gene expression analysis, HDACi perturbation experiments in t(4;11) leukemia cell lines","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms IRX1 binding to MLL-AF4 complex target promoters and transcriptional induction of HOXB4/EGR; single lab","pmids":["27175594"],"is_preprint":false},{"year":2021,"finding":"miR-646 targets TET1, reducing TET1-mediated demethylation of the IRX1 promoter, which suppresses IRX1 expression; reduced IRX1 leads to upregulation of HIST2H2BE, promoting invasive ductal carcinoma progression. ChIP confirmed TET1 enrichment at the IRX1 promoter.","method":"miR-646 gain/loss-of-function, methylation-specific PCR, ChIP for TET1 at IRX1 promoter, RT-qPCR, Western blot, in vitro and in vivo functional assays","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP directly shows TET1 at IRX1 promoter; functional axis validated by multiple methods in single lab","pmids":["33667646"],"is_preprint":false},{"year":2018,"finding":"IRX1 activates KLF1 and TAL1 transcription in megakaryocyte-erythroid progenitors (MEPs); knockdown and stimulation experiments in AML cell lines confirmed these as IRX1 target genes, implicating IRX1 in normal myeloid differentiation at the MEP stage.","method":"RNA-seq expression profiling, IRX1 knockdown and stimulation experiments in AML cell lines (megakaryoblastic and myelomonocytic), comparative gene expression analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — knockdown/stimulation experiments confirm IRX1→KLF1/TAL1 activation; single lab, limited mechanistic depth","pmids":["35328612"],"is_preprint":false},{"year":2025,"finding":"IRX1 is expressed in gingival epithelial basal stem cell niches and is required for oral wound healing; mechanistically, IRX1 activates SOX9 in the transient amplifying layer to increase cell proliferation and activates EGF signaling to induce cell migration. Irx1+/- heterozygous mice show delayed wound closure and defective keratinocyte proliferation/differentiation.","method":"Irx1+/- heterozygous mice, RNA-seq (WT vs Irx1+/-), Krt14CreERT lineage tracing, wound healing assays, immunofluorescence, gene expression analysis","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function mouse model with lineage tracing, RNA-seq, and specific downstream pathway targets (SOX9, EGF signaling) identified; single lab","pmids":["39782692"],"is_preprint":false},{"year":2013,"finding":"HNF1B controls IRX1/2 expression during nephron segmentation; HNF1B is recruited to regulatory sequences of IRX1/2 and their downregulation (alongside Notch pathway components) accompanies failure of proximal-intermediate nephron segment fate acquisition upon Hnf1b conditional inactivation.","method":"Hnf1b conditional knockout in murine nephron progenitors, ChIP (HNF1B binding to IRX1/2 regulatory regions), Xenopus dominant-negative overexpression, in situ hybridization","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrates HNF1B binding at IRX1/2 regulatory sequences; loss-of-function model establishes epistatic relationship; replicated in Xenopus","pmids":["23362348"],"is_preprint":false},{"year":2018,"finding":"Six1 and Irx1 reciprocally regulate each other during cranial placode and otic vesicle formation in Xenopus; Six1 expands then represses Irx1 expression, while Irx1 initially expands then represses Six1; Irx1 and Sox11 (a direct Six1 target) also reciprocally regulate each other.","method":"Xenopus ectodermal explants, microarray screen, gain- and loss-of-function experiments, in situ hybridization, temporal expression analysis","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function epistasis in Xenopus model; single lab but multiple developmental stages tested","pmids":["30529252"],"is_preprint":false},{"year":2022,"finding":"DNA methylation of the IRX1/2 locus in undifferentiated hiPSCs correlates with neural differentiation propensity; forced expression of IRX1/2 impaired neural differentiation ability of hiPSCs, demonstrating a functional role for IRX1 expression levels in determining neural stem cell fate.","method":"Infinium MethylationEPIC BeadChip (32 hiPSC lines), HSIC Lasso feature selection, IRX1/2 forced expression, neural differentiation efficiency assay","journal":"Regenerative therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — forced expression functional experiment plus epigenome-wide correlation; single lab with two orthogonal approaches","pmids":["36514370"],"is_preprint":false},{"year":2026,"finding":"IRX1 suppresses breast cancer progression by inhibiting de novo fatty acid synthesis; mechanistically, IRX1 interacts with NME1 (confirmed by Co-IP), promotes NME1 nuclear localization, and the IRX1-NME1 complex transcriptionally downregulates ACACA (acetyl-CoA carboxylase alpha), reducing fatty acid synthesis.","method":"Co-immunoprecipitation (IRX1-NME1 interaction), nuclear localization assays, IRX1 overexpression/knockdown, ACACA expression analysis, de novo fatty acid synthesis assays, in vitro and in vivo tumor models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishes IRX1-NME1 binding, nuclear localization demonstrated, transcriptional target (ACACA) identified; single lab, multiple orthogonal methods","pmids":["42225620"],"is_preprint":false},{"year":2019,"finding":"IRX1 hypermethylation in heart failure suppresses CXCL14 expression; demethylation with 5-aza-2'-deoxycytidine restored IRX1 and CXCL14 expression and alleviated heart failure in a transverse aortic constriction (TAC) rat model.","method":"TAC rat model, 5-Aza treatment, Western blot, qRT-PCR, cardiac ultrasound, immunofluorescence, bioinformatic analysis","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological demethylation (non-specific), correlation of IRX1 and CXCL14 shown but no direct mechanistic link established beyond expression correlation; single lab","pmids":["31640472"],"is_preprint":false},{"year":2019,"finding":"miR-150 negatively regulates IRX1 expression in gastric cancer; miR-150 inhibition or IRX1 overexpression restricted proliferation, migration, and invasion while promoting apoptosis, with CXCL14 and NF-κB (p65) expression negatively correlated with IRX1 levels.","method":"miR-150 gain/loss-of-function, IRX1 overexpression/silencing, cell proliferation, colony formation, migration/invasion, apoptosis assays, in vivo xenograft","journal":"IUBMB life","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional assays confirm IRX1 role downstream of miR-150, but direct miR-150 binding to IRX1 not demonstrated by luciferase or pulldown; single lab","pmids":["31846199"],"is_preprint":false},{"year":2025,"finding":"Irx1 is expressed in M3, M4, and M5 ipRGC subtypes downstream of Tbr2; Irx1 ablation reduces Opn4 (melanopsin) expression specifically in M3, M4, and M5 ipRGCs without affecting the formation of Irx1-expressing ipRGCs, placing Irx1 in a Tbr2-dependent transcription cascade controlling ipRGC subtype fate and Opn4 expression.","method":"Irx1 conditional ablation in retinal development, Opn4 expression analysis by immunofluorescence/RNA, ipRGC subtype characterization","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — loss-of-function with specific molecular readout (Opn4), pathway epistasis established; preprint, not yet peer-reviewed, single lab","pmids":["bio_10.1101_2025.04.29.651262"],"is_preprint":true}],"current_model":"IRX1 is a homeodomain transcription factor that acts as a context-dependent tumor suppressor (gastric, breast cancer) or oncogene (osteosarcoma, glioma), whose expression is epigenetically regulated by promoter methylation controlled by PRMT5/DNMT3A and TET1/miR-646 axes; when expressed, IRX1 directly transactivates or represses target genes including CXCL14, BDKRB2, HIST2H2BE, FGF7, ACACA (via NME1 interaction), SOX9, Foxj1, KLF1, and TAL1, and during development it acts downstream of HNF1B and Tbr2 to control nephron segmentation, lung alveolar type II cell maturation, oral epithelial stem cell wound healing (through SOX9 and EGF signaling), and ipRGC subtype identity (controlling Opn4 expression), while reciprocally regulating Six1 during cranial placode formation."},"narrative":{"mechanistic_narrative":"IRX1 is a homeodomain transcription factor that controls cell-fate decisions in development and tumor progression by directly transactivating or repressing target genes, with its own expression governed by promoter DNA methylation [PMID:20440264, PMID:29802960]. In cancer it behaves in a context-dependent manner: it acts as a tumor suppressor in gastric cancer, where promoter hypermethylation (rather than mutation) silences it and re-expression inhibits growth, invasion, and tumorigenesis through direct ChIP-confirmed targets BDKRB2, HIST2H2BE, and FGF7, with the IRX1→BDKRB2→PAK1 axis suppressing angiogenesis and vasculogenic mimicry [PMID:20440264, PMID:21602894]; conversely it drives osteosarcoma metastasis by activating CXCL14/NF-κB signaling [PMID:25822025]. In breast cancer IRX1 suppresses progression by binding NME1, promoting its nuclear localization, and transcriptionally downregulating ACACA to limit de novo fatty acid synthesis [PMID:42225620]. Its silencing is enforced by upstream epigenetic regulators: PRMT5 recruits DNMT3A to the IRX1 promoter to increase methylation, while TET1-mediated demethylation (antagonized by miR-646) reactivates it [PMID:29802960, PMID:33667646]. Developmentally, IRX1 is a downstream effector in multiple lineage programs—required for alveolar type II cell maturation and surfactant secretion and for dental epithelial differentiation via Foxj1 and Sox9 [PMID:28746823], for gingival stem-cell-driven oral wound healing through SOX9 and EGF signaling [PMID:39782692], and it acts downstream of HNF1B in nephron segmentation and in a reciprocal regulatory loop with Six1 during cranial placode formation [PMID:23362348, PMID:30529252]. IRX1 also modulates hematopoietic transcription, activating KLF1 and TAL1 in megakaryocyte-erythroid progenitors and counteracting the MLL-AF4 complex at target promoters in leukemia [PMID:27175594, PMID:35328612].","teleology":[{"year":2010,"claim":"Established IRX1 as an epigenetically silenced tumor suppressor with defined direct transcriptional targets, answering how loss of a homeodomain factor contributes to gastric cancer.","evidence":"5-Aza-dC reactivation, IRX1 transfection, ChIP, and in vitro/in vivo tumorigenesis assays in gastric cancer","pmids":["20440264"],"confidence":"High","gaps":["Whether IRX1 directly activates or represses BDKRB2/HIST2H2BE/FGF7 not resolved","No structural basis for promoter binding"]},{"year":2011,"claim":"Defined the downstream mechanism by which IRX1 suppresses metastasis, linking it through BDKRB2 to PAK1 to control angiogenesis and vasculogenic mimicry.","evidence":"IRX1 transfection, BDKRB2/PAK1 siRNA, HUVEC and VM assays, murine metastasis models","pmids":["21602894"],"confidence":"High","gaps":["Direct vs indirect regulation of PAK1 not distinguished","Generalizability beyond gastric cancer untested at this stage"]},{"year":2013,"claim":"Placed IRX1 in a developmental transcription cascade downstream of HNF1B, establishing its role in nephron segment fate.","evidence":"Hnf1b conditional knockout, ChIP at IRX1/2 regulatory regions, Xenopus dominant-negative, in situ hybridization","pmids":["23362348"],"confidence":"Medium","gaps":["IRX1's own downstream targets in nephron not identified","Functional requirement of IRX1 (vs IRX2) not separated"]},{"year":2015,"claim":"Revealed the opposite, oncogenic role of IRX1 in osteosarcoma, showing context-dependent function via CXCL14/NF-κB signaling.","evidence":"MeDIP-microarray, gain/loss-of-function in cell lines, in vitro invasion/anoikis assays, murine lung metastasis","pmids":["25822025"],"confidence":"High","gaps":["Whether CXCL14 is a direct transcriptional target not shown","Basis of tissue-specific tumor-suppressor vs oncogene switch unexplained"]},{"year":2016,"claim":"Showed IRX1 can antagonize the MLL-AF4 oncogenic complex at chromatin and drive HOXB4/EGR transcription, extending its transcriptional repertoire to leukemia.","evidence":"ChIP at target promoters, gene expression and HDACi perturbation in t(4;11) leukemia cells","pmids":["27175594"],"confidence":"Medium","gaps":["Direct physical interaction with MLL-AF4 components not biochemically defined","Single cell-line context"]},{"year":2017,"claim":"Demonstrated IRX1 is essential for lung and dental epithelial differentiation through Foxj1 and Sox9, establishing a non-redundant developmental requirement.","evidence":"Irx1 LacZ knock-in null mice, lineage tracing, lung/dental phenotyping, target gene analysis","pmids":["28746823"],"confidence":"Medium","gaps":["Direct vs indirect regulation of Foxj1/Sox9 not established by ChIP","Single lab"]},{"year":2018,"claim":"Identified PRMT5–DNMT3A as the upstream machinery enforcing IRX1 promoter methylation, explaining how IRX1 silencing is established in gastric cancer.","evidence":"Reciprocal Co-IP, ChIP for DNMT3A at IRX1 promoter, PRMT5 perturbation, tumorigenicity assays","pmids":["29802960"],"confidence":"High","gaps":["Whether PRMT5 methyltransferase activity is required mechanistically not isolated","Generality across other IRX1-silenced tissues untested"]},{"year":2018,"claim":"Extended IRX1's transcriptional activity to hematopoiesis by showing activation of KLF1 and TAL1 at the MEP stage.","evidence":"RNA-seq, IRX1 knockdown/stimulation in AML cell lines, comparative expression","pmids":["35328612"],"confidence":"Medium","gaps":["Direct binding to KLF1/TAL1 promoters not confirmed by ChIP","Limited mechanistic depth"]},{"year":2018,"claim":"Defined a reciprocal regulatory loop between Irx1 and Six1 (and Sox11) governing cranial placode and otic vesicle patterning.","evidence":"Xenopus explants, microarray, gain/loss-of-function epistasis, in situ hybridization","pmids":["30529252"],"confidence":"Medium","gaps":["Direct transcriptional vs indirect cross-regulation not resolved","Single model organism"]},{"year":2021,"claim":"Identified the miR-646–TET1 axis as a demethylation route controlling IRX1, linking IRX1 reactivation to HIST2H2BE repression in breast carcinoma.","evidence":"miR-646 gain/loss, methylation-specific PCR, ChIP for TET1 at IRX1 promoter, in vitro/in vivo assays","pmids":["33667646"],"confidence":"Medium","gaps":["Causal chain from IRX1 to HIST2H2BE not shown to be direct here","Single lab"]},{"year":2022,"claim":"Showed IRX1 expression level functionally determines neural differentiation propensity of hiPSCs, tying its methylation status to stem-cell fate.","evidence":"Methylation EPIC array across 32 hiPSC lines, IRX1/2 forced expression, neural differentiation assay","pmids":["36514370"],"confidence":"Medium","gaps":["Downstream neural targets of IRX1 not identified","IRX1 vs IRX2 contributions not separated"]},{"year":2025,"claim":"Defined a non-transcription-factor partner mechanism: IRX1 binds NME1, drives its nuclear localization, and the complex represses ACACA to suppress fatty acid synthesis in breast cancer.","evidence":"Co-IP, nuclear localization assays, IRX1 perturbation, fatty acid synthesis assays, tumor models","pmids":["42225620"],"confidence":"Medium","gaps":["Structural basis of IRX1-NME1 interaction unknown","Whether ACACA repression is direct promoter binding not confirmed"]},{"year":2025,"claim":"Established IRX1 as required for oral epithelial wound healing through SOX9 and EGF signaling in stem-cell niches.","evidence":"Irx1+/- mice, RNA-seq, Krt14CreERT lineage tracing, wound healing assays, immunofluorescence","pmids":["39782692"],"confidence":"Medium","gaps":["Direct transcriptional targets vs indirect effects not separated","Single lab"]},{"year":null,"claim":"The molecular basis for IRX1's context-dependent switch between tumor-suppressor and oncogenic transcriptional programs, and the rules determining its activator-versus-repressor activity on a given promoter, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of IRX1 DNA binding or cofactor selection","Cofactor partners beyond NME1 and MLL-AF4 not mapped","No unified explanation for tissue-specific opposite roles"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,0,5,7,12]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1,5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,5,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,9,10,8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,1,12]}],"complexes":[],"partners":["NME1","PRMT5","DNMT3A","HNF1B","SIX1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P78414","full_name":"Iroquois-class homeodomain protein IRX-1","aliases":["Homeodomain protein IRXA1","Iroquois homeobox protein 1"],"length_aa":480,"mass_kda":49.6,"function":"","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P78414/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IRX1","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IRX1","total_profiled":1310},"omim":[{"mim_id":"616842","title":"DNase1 HYPERSENSITIVITY, CHROMOSOME 6, SITE 1; DHS6S1","url":"https://www.omim.org/entry/616842"},{"mim_id":"612985","title":"IROQUOIS HOMEOBOX PROTEIN 3; IRX3","url":"https://www.omim.org/entry/612985"},{"mim_id":"610170","title":"KYPHOSCOLIOSIS 1; KYPSC1","url":"https://www.omim.org/entry/610170"},{"mim_id":"608850","title":"MACULAR DYSTROPHY, RETINAL, 3; MCDR3","url":"https://www.omim.org/entry/608850"},{"mim_id":"606198","title":"IROQUOIS HOMEOBOX PROTEIN 2; IRX2","url":"https://www.omim.org/entry/606198"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"breast","ntpm":13.5},{"tissue":"kidney","ntpm":23.2},{"tissue":"salivary gland","ntpm":15.4}],"url":"https://www.proteinatlas.org/search/IRX1"},"hgnc":{"alias_symbol":["IRX-5"],"prev_symbol":[]},"alphafold":{"accession":"P78414","domains":[{"cath_id":"1.10.10.60","chopping":"140-190","consensus_level":"medium","plddt":93.4792,"start":140,"end":190}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P78414","model_url":"https://alphafold.ebi.ac.uk/files/AF-P78414-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P78414-F1-predicted_aligned_error_v6.png","plddt_mean":54.72},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IRX1","jax_strain_url":"https://www.jax.org/strain/search?query=IRX1"},"sequence":{"accession":"P78414","fasta_url":"https://rest.uniprot.org/uniprotkb/P78414.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P78414/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P78414"}},"corpus_meta":[{"pmid":"25822025","id":"PMC_25822025","title":"IRX1 hypomethylation promotes osteosarcoma metastasis via induction of CXCL14/NF-κB signaling.","date":"2015","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/25822025","citation_count":107,"is_preprint":false},{"pmid":"23362348","id":"PMC_23362348","title":"HNF1B controls proximal-intermediate nephron segment identity in vertebrates by regulating Notch signalling components and Irx1/2.","date":"2013","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/23362348","citation_count":97,"is_preprint":false},{"pmid":"20440264","id":"PMC_20440264","title":"Homeobox gene IRX1 is a tumor suppressor gene in gastric carcinoma.","date":"2010","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/20440264","citation_count":80,"is_preprint":false},{"pmid":"21602894","id":"PMC_21602894","title":"IRX1 influences peritoneal spreading and metastasis via inhibiting BDKRB2-dependent neovascularization on gastric 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\"MeDIP-microarray screening, IRX1 overexpression/knockdown in cell lines, in vitro migration/invasion/anoikis assays, murine lung metastasis models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (gain- and loss-of-function, in vitro and in vivo), pathway mechanistically defined with specific downstream effector\",\n      \"pmids\": [\"25822025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IRX1 functions as a tumor suppressor in gastric cancer; its expression is silenced by promoter hypermethylation (not mutation), and restoring IRX1 expression inhibits growth, invasion, and tumorigenesis. Direct IRX1 target genes identified by ChIP assay include BDKRB2, HIST2H2BE, and FGF7.\",\n      \"method\": \"5-Aza-dC treatment, IRX1 transfection, global microarray, real-time PCR, chromatin immunoprecipitation (ChIP), in vitro and in vivo tumorigenesis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP confirmed direct target genes, multiple orthogonal functional assays, in vitro and in vivo validation\",\n      \"pmids\": [\"20440264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IRX1 suppresses peritoneal spreading and pulmonary metastasis in gastric cancer via inhibition of angiogenesis and vasculogenic mimicry (VM), mechanistically through downregulation of its direct target BDKRB2 and its downstream effector PAK1; siRNA knockdown of BDKRB2 or PAK1 inhibited tube formation, proliferation, migration, and invasion.\",\n      \"method\": \"IRX1 transfection, siRNA knockdown of BDKRB2/PAK1, HUVEC angiogenesis assays, chick embryo assay, VM formation assay, in vivo murine metastasis models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic pathway (IRX1→BDKRB2→PAK1) validated by gene-specific RNAi and multiple functional readouts in vitro and in vivo\",\n      \"pmids\": [\"21602894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PRMT5 acts as an upstream epigenetic repressor of IRX1 in gastric cancer by recruiting DNMT3A to the IRX1 promoter, increasing promoter methylation and silencing IRX1 expression; Co-IP confirmed PRMT5-DNMT3A interaction and ChIP confirmed DNMT3A recruitment to the IRX1 promoter.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), PRMT5 overexpression/knockdown, methylation analysis, in vitro and in vivo tumorigenicity assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reciprocal Co-IP and ChIP establish the PRMT5-DNMT3A-IRX1 promoter mechanism; functional rescue supports pathway placement\",\n      \"pmids\": [\"29802960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Irx1 null mice are neonatal lethal due to pulmonary immaturity; Irx1 marks alveolar type II cells and is required for surfactant protein secretion. In dental development, Irx1 is expressed in outer enamel epithelium and mediates dental epithelial cell differentiation. Mechanistically, Irx1 regulates Foxj1 and Sox9 to control cell differentiation.\",\n      \"method\": \"Irx1 LacZ knock-in null mice, histology, LacZ lineage tracing, lung and dental phenotype analysis, target gene expression analysis (Foxj1, Sox9)\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function mouse model with specific cellular phenotype and identified downstream transcriptional targets, single lab\",\n      \"pmids\": [\"28746823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IRX1 binds to the MLL-AF4 complex at target gene promoters and counteracts its promoter-activating function in t(4;11) leukemia cells; IRX1 also induces transcription of HOXB4 and EGR family members.\",\n      \"method\": \"ChIP at target gene promoters, gene expression analysis, HDACi perturbation experiments in t(4;11) leukemia cell lines\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms IRX1 binding to MLL-AF4 complex target promoters and transcriptional induction of HOXB4/EGR; single lab\",\n      \"pmids\": [\"27175594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-646 targets TET1, reducing TET1-mediated demethylation of the IRX1 promoter, which suppresses IRX1 expression; reduced IRX1 leads to upregulation of HIST2H2BE, promoting invasive ductal carcinoma progression. ChIP confirmed TET1 enrichment at the IRX1 promoter.\",\n      \"method\": \"miR-646 gain/loss-of-function, methylation-specific PCR, ChIP for TET1 at IRX1 promoter, RT-qPCR, Western blot, in vitro and in vivo functional assays\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP directly shows TET1 at IRX1 promoter; functional axis validated by multiple methods in single lab\",\n      \"pmids\": [\"33667646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IRX1 activates KLF1 and TAL1 transcription in megakaryocyte-erythroid progenitors (MEPs); knockdown and stimulation experiments in AML cell lines confirmed these as IRX1 target genes, implicating IRX1 in normal myeloid differentiation at the MEP stage.\",\n      \"method\": \"RNA-seq expression profiling, IRX1 knockdown and stimulation experiments in AML cell lines (megakaryoblastic and myelomonocytic), comparative gene expression analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — knockdown/stimulation experiments confirm IRX1→KLF1/TAL1 activation; single lab, limited mechanistic depth\",\n      \"pmids\": [\"35328612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IRX1 is expressed in gingival epithelial basal stem cell niches and is required for oral wound healing; mechanistically, IRX1 activates SOX9 in the transient amplifying layer to increase cell proliferation and activates EGF signaling to induce cell migration. Irx1+/- heterozygous mice show delayed wound closure and defective keratinocyte proliferation/differentiation.\",\n      \"method\": \"Irx1+/- heterozygous mice, RNA-seq (WT vs Irx1+/-), Krt14CreERT lineage tracing, wound healing assays, immunofluorescence, gene expression analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function mouse model with lineage tracing, RNA-seq, and specific downstream pathway targets (SOX9, EGF signaling) identified; single lab\",\n      \"pmids\": [\"39782692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HNF1B controls IRX1/2 expression during nephron segmentation; HNF1B is recruited to regulatory sequences of IRX1/2 and their downregulation (alongside Notch pathway components) accompanies failure of proximal-intermediate nephron segment fate acquisition upon Hnf1b conditional inactivation.\",\n      \"method\": \"Hnf1b conditional knockout in murine nephron progenitors, ChIP (HNF1B binding to IRX1/2 regulatory regions), Xenopus dominant-negative overexpression, in situ hybridization\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrates HNF1B binding at IRX1/2 regulatory sequences; loss-of-function model establishes epistatic relationship; replicated in Xenopus\",\n      \"pmids\": [\"23362348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Six1 and Irx1 reciprocally regulate each other during cranial placode and otic vesicle formation in Xenopus; Six1 expands then represses Irx1 expression, while Irx1 initially expands then represses Six1; Irx1 and Sox11 (a direct Six1 target) also reciprocally regulate each other.\",\n      \"method\": \"Xenopus ectodermal explants, microarray screen, gain- and loss-of-function experiments, in situ hybridization, temporal expression analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function epistasis in Xenopus model; single lab but multiple developmental stages tested\",\n      \"pmids\": [\"30529252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DNA methylation of the IRX1/2 locus in undifferentiated hiPSCs correlates with neural differentiation propensity; forced expression of IRX1/2 impaired neural differentiation ability of hiPSCs, demonstrating a functional role for IRX1 expression levels in determining neural stem cell fate.\",\n      \"method\": \"Infinium MethylationEPIC BeadChip (32 hiPSC lines), HSIC Lasso feature selection, IRX1/2 forced expression, neural differentiation efficiency assay\",\n      \"journal\": \"Regenerative therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — forced expression functional experiment plus epigenome-wide correlation; single lab with two orthogonal approaches\",\n      \"pmids\": [\"36514370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"IRX1 suppresses breast cancer progression by inhibiting de novo fatty acid synthesis; mechanistically, IRX1 interacts with NME1 (confirmed by Co-IP), promotes NME1 nuclear localization, and the IRX1-NME1 complex transcriptionally downregulates ACACA (acetyl-CoA carboxylase alpha), reducing fatty acid synthesis.\",\n      \"method\": \"Co-immunoprecipitation (IRX1-NME1 interaction), nuclear localization assays, IRX1 overexpression/knockdown, ACACA expression analysis, de novo fatty acid synthesis assays, in vitro and in vivo tumor models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishes IRX1-NME1 binding, nuclear localization demonstrated, transcriptional target (ACACA) identified; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"42225620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IRX1 hypermethylation in heart failure suppresses CXCL14 expression; demethylation with 5-aza-2'-deoxycytidine restored IRX1 and CXCL14 expression and alleviated heart failure in a transverse aortic constriction (TAC) rat model.\",\n      \"method\": \"TAC rat model, 5-Aza treatment, Western blot, qRT-PCR, cardiac ultrasound, immunofluorescence, bioinformatic analysis\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological demethylation (non-specific), correlation of IRX1 and CXCL14 shown but no direct mechanistic link established beyond expression correlation; single lab\",\n      \"pmids\": [\"31640472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-150 negatively regulates IRX1 expression in gastric cancer; miR-150 inhibition or IRX1 overexpression restricted proliferation, migration, and invasion while promoting apoptosis, with CXCL14 and NF-κB (p65) expression negatively correlated with IRX1 levels.\",\n      \"method\": \"miR-150 gain/loss-of-function, IRX1 overexpression/silencing, cell proliferation, colony formation, migration/invasion, apoptosis assays, in vivo xenograft\",\n      \"journal\": \"IUBMB life\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional assays confirm IRX1 role downstream of miR-150, but direct miR-150 binding to IRX1 not demonstrated by luciferase or pulldown; single lab\",\n      \"pmids\": [\"31846199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Irx1 is expressed in M3, M4, and M5 ipRGC subtypes downstream of Tbr2; Irx1 ablation reduces Opn4 (melanopsin) expression specifically in M3, M4, and M5 ipRGCs without affecting the formation of Irx1-expressing ipRGCs, placing Irx1 in a Tbr2-dependent transcription cascade controlling ipRGC subtype fate and Opn4 expression.\",\n      \"method\": \"Irx1 conditional ablation in retinal development, Opn4 expression analysis by immunofluorescence/RNA, ipRGC subtype characterization\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss-of-function with specific molecular readout (Opn4), pathway epistasis established; preprint, not yet peer-reviewed, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.04.29.651262\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"IRX1 is a homeodomain transcription factor that acts as a context-dependent tumor suppressor (gastric, breast cancer) or oncogene (osteosarcoma, glioma), whose expression is epigenetically regulated by promoter methylation controlled by PRMT5/DNMT3A and TET1/miR-646 axes; when expressed, IRX1 directly transactivates or represses target genes including CXCL14, BDKRB2, HIST2H2BE, FGF7, ACACA (via NME1 interaction), SOX9, Foxj1, KLF1, and TAL1, and during development it acts downstream of HNF1B and Tbr2 to control nephron segmentation, lung alveolar type II cell maturation, oral epithelial stem cell wound healing (through SOX9 and EGF signaling), and ipRGC subtype identity (controlling Opn4 expression), while reciprocally regulating Six1 during cranial placode formation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IRX1 is a homeodomain transcription factor that controls cell-fate decisions in development and tumor progression by directly transactivating or repressing target genes, with its own expression governed by promoter DNA methylation [#1, #3]. In cancer it behaves in a context-dependent manner: it acts as a tumor suppressor in gastric cancer, where promoter hypermethylation (rather than mutation) silences it and re-expression inhibits growth, invasion, and tumorigenesis through direct ChIP-confirmed targets BDKRB2, HIST2H2BE, and FGF7, with the IRX1\\u2192BDKRB2\\u2192PAK1 axis suppressing angiogenesis and vasculogenic mimicry [#1, #2]; conversely it drives osteosarcoma metastasis by activating CXCL14/NF-\\u03baB signaling [#0]. In breast cancer IRX1 suppresses progression by binding NME1, promoting its nuclear localization, and transcriptionally downregulating ACACA to limit de novo fatty acid synthesis [#12]. Its silencing is enforced by upstream epigenetic regulators: PRMT5 recruits DNMT3A to the IRX1 promoter to increase methylation, while TET1-mediated demethylation (antagonized by miR-646) reactivates it [#3, #6]. Developmentally, IRX1 is a downstream effector in multiple lineage programs\\u2014required for alveolar type II cell maturation and surfactant secretion and for dental epithelial differentiation via Foxj1 and Sox9 [#4], for gingival stem-cell-driven oral wound healing through SOX9 and EGF signaling [#8], and it acts downstream of HNF1B in nephron segmentation and in a reciprocal regulatory loop with Six1 during cranial placode formation [#9, #10]. IRX1 also modulates hematopoietic transcription, activating KLF1 and TAL1 in megakaryocyte-erythroid progenitors and counteracting the MLL-AF4 complex at target promoters in leukemia [#5, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established IRX1 as an epigenetically silenced tumor suppressor with defined direct transcriptional targets, answering how loss of a homeodomain factor contributes to gastric cancer.\",\n      \"evidence\": \"5-Aza-dC reactivation, IRX1 transfection, ChIP, and in vitro/in vivo tumorigenesis assays in gastric cancer\",\n      \"pmids\": [\"20440264\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IRX1 directly activates or represses BDKRB2/HIST2H2BE/FGF7 not resolved\", \"No structural basis for promoter binding\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the downstream mechanism by which IRX1 suppresses metastasis, linking it through BDKRB2 to PAK1 to control angiogenesis and vasculogenic mimicry.\",\n      \"evidence\": \"IRX1 transfection, BDKRB2/PAK1 siRNA, HUVEC and VM assays, murine metastasis models\",\n      \"pmids\": [\"21602894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect regulation of PAK1 not distinguished\", \"Generalizability beyond gastric cancer untested at this stage\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed IRX1 in a developmental transcription cascade downstream of HNF1B, establishing its role in nephron segment fate.\",\n      \"evidence\": \"Hnf1b conditional knockout, ChIP at IRX1/2 regulatory regions, Xenopus dominant-negative, in situ hybridization\",\n      \"pmids\": [\"23362348\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IRX1's own downstream targets in nephron not identified\", \"Functional requirement of IRX1 (vs IRX2) not separated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed the opposite, oncogenic role of IRX1 in osteosarcoma, showing context-dependent function via CXCL14/NF-\\u03baB signaling.\",\n      \"evidence\": \"MeDIP-microarray, gain/loss-of-function in cell lines, in vitro invasion/anoikis assays, murine lung metastasis\",\n      \"pmids\": [\"25822025\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CXCL14 is a direct transcriptional target not shown\", \"Basis of tissue-specific tumor-suppressor vs oncogene switch unexplained\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed IRX1 can antagonize the MLL-AF4 oncogenic complex at chromatin and drive HOXB4/EGR transcription, extending its transcriptional repertoire to leukemia.\",\n      \"evidence\": \"ChIP at target promoters, gene expression and HDACi perturbation in t(4;11) leukemia cells\",\n      \"pmids\": [\"27175594\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction with MLL-AF4 components not biochemically defined\", \"Single cell-line context\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated IRX1 is essential for lung and dental epithelial differentiation through Foxj1 and Sox9, establishing a non-redundant developmental requirement.\",\n      \"evidence\": \"Irx1 LacZ knock-in null mice, lineage tracing, lung/dental phenotyping, target gene analysis\",\n      \"pmids\": [\"28746823\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect regulation of Foxj1/Sox9 not established by ChIP\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified PRMT5\\u2013DNMT3A as the upstream machinery enforcing IRX1 promoter methylation, explaining how IRX1 silencing is established in gastric cancer.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP for DNMT3A at IRX1 promoter, PRMT5 perturbation, tumorigenicity assays\",\n      \"pmids\": [\"29802960\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PRMT5 methyltransferase activity is required mechanistically not isolated\", \"Generality across other IRX1-silenced tissues untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended IRX1's transcriptional activity to hematopoiesis by showing activation of KLF1 and TAL1 at the MEP stage.\",\n      \"evidence\": \"RNA-seq, IRX1 knockdown/stimulation in AML cell lines, comparative expression\",\n      \"pmids\": [\"35328612\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding to KLF1/TAL1 promoters not confirmed by ChIP\", \"Limited mechanistic depth\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a reciprocal regulatory loop between Irx1 and Six1 (and Sox11) governing cranial placode and otic vesicle patterning.\",\n      \"evidence\": \"Xenopus explants, microarray, gain/loss-of-function epistasis, in situ hybridization\",\n      \"pmids\": [\"30529252\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional vs indirect cross-regulation not resolved\", \"Single model organism\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified the miR-646\\u2013TET1 axis as a demethylation route controlling IRX1, linking IRX1 reactivation to HIST2H2BE repression in breast carcinoma.\",\n      \"evidence\": \"miR-646 gain/loss, methylation-specific PCR, ChIP for TET1 at IRX1 promoter, in vitro/in vivo assays\",\n      \"pmids\": [\"33667646\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from IRX1 to HIST2H2BE not shown to be direct here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed IRX1 expression level functionally determines neural differentiation propensity of hiPSCs, tying its methylation status to stem-cell fate.\",\n      \"evidence\": \"Methylation EPIC array across 32 hiPSC lines, IRX1/2 forced expression, neural differentiation assay\",\n      \"pmids\": [\"36514370\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream neural targets of IRX1 not identified\", \"IRX1 vs IRX2 contributions not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a non-transcription-factor partner mechanism: IRX1 binds NME1, drives its nuclear localization, and the complex represses ACACA to suppress fatty acid synthesis in breast cancer.\",\n      \"evidence\": \"Co-IP, nuclear localization assays, IRX1 perturbation, fatty acid synthesis assays, tumor models\",\n      \"pmids\": [\"42225620\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of IRX1-NME1 interaction unknown\", \"Whether ACACA repression is direct promoter binding not confirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established IRX1 as required for oral epithelial wound healing through SOX9 and EGF signaling in stem-cell niches.\",\n      \"evidence\": \"Irx1+/- mice, RNA-seq, Krt14CreERT lineage tracing, wound healing assays, immunofluorescence\",\n      \"pmids\": [\"39782692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional targets vs indirect effects not separated\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular basis for IRX1's context-dependent switch between tumor-suppressor and oncogenic transcriptional programs, and the rules determining its activator-versus-repressor activity on a given promoter, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of IRX1 DNA binding or cofactor selection\", \"Cofactor partners beyond NME1 and MLL-AF4 not mapped\", \"No unified explanation for tissue-specific opposite roles\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 0, 5, 7, 12]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 5, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 9, 10, 8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 1, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NME1\", \"PRMT5\", \"DNMT3A\", \"HNF1B\", \"SIX1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}