{"gene":"MEOX1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2014,"finding":"In zebrafish, meox1 specifies endotomal endothelial precursor cells within a sub-compartment of the nascent somite (the endotome); these cells migrate to colonize the dorsal aorta and induce haematopoietic stem cell formation via chemokine signalling. Loss of meox1 expands the endotome at the expense of muscle precursors (external cell layer), generating excess endotome-derived cells in the dorsal aorta and a dramatic increase in HSC induction.","method":"Zebrafish loss-of-function genetics, lineage tracing, live imaging, epistasis with chemokine pathway mutants","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetics, lineage tracing, live imaging, epistasis) in a high-profile publication; findings mechanistically link meox1 to endotome specification and HSC induction pathway","pmids":["25119043"],"is_preprint":false},{"year":2017,"finding":"Meox1 directly inhibits the cell-cycle checkpoint gene ccnb1 (cyclin B1), thereby initiating G2 cell-cycle arrest within muscle stem cells. Disrupting this G2 arrest causes premature lineage commitment and defects in muscle growth. This establishes a Meox1→ccnb1 repression axis governing muscle stem cell dynamics during zebrafish myotome growth.","method":"Zebrafish genetics, clonal analysis, chromatin binding assays (direct inhibition of ccnb1 promoter), rescue experiments with ccnb1 overexpression","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding to ccnb1 promoter demonstrated, zebrafish genetic loss-of-function with defined cellular phenotype, rescue experiments; independently corroborated in Sebastes schlegelii (PMID:38732090)","pmids":["28686860"],"is_preprint":false},{"year":2009,"finding":"Meox1 occupies conserved promoter regions of the transcription factor genes Tbx18 and Uncx (as well as the previously known target Bapx1) in the sclerotome, as shown by chromatin immunoprecipitation. Loss of Meox1 in mice alters relative cell proliferation rates in the rostral vs. caudal sclerotome, disrupts rostro-caudal polarity, and causes atlas-to-basioccipital assimilation—demonstrating a non-redundant role for Meox1 in maintaining sclerotome polarity through direct transcriptional regulation of downstream transcription factors.","method":"Mouse homozygous knockout, chromatin immunoprecipitation (ChIP) for conserved promoter elements, proliferation assays, gene expression analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP for direct promoter occupancy combined with mouse KO phenotypic analysis and expression studies, rigorous mechanistic dissection in a focused study","pmids":["19520072"],"is_preprint":false},{"year":2011,"finding":"MEOX1 (and MEOX2) activate p16(INK4a) expression in a DNA-binding-dependent manner, whereas they induce p21(CIP1/WAF1) in a DNA-binding-independent manner, both leading to G1/S cell-cycle arrest and endothelial cell senescence. This demonstrates mechanistically distinct modes of transcriptional activation for two CDK inhibitor target genes.","method":"Overexpression of wild-type vs. DNA-binding-deficient MEOX1/MEOX2 mutants in vascular endothelial cells; cell cycle and senescence assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site/DNA-binding mutagenesis with functional readout (cell cycle arrest, senescence), two orthogonal mechanistic conclusions from same study","pmids":["22206000"],"is_preprint":false},{"year":2011,"finding":"Meox1 is a direct transcriptional target of Hoxa2 in the second branchial arch: Hoxa2 binds two conserved sites in the Meox1 proximal promoter by ChIP, and these sites are required for Hoxa2-dependent Meox1 promoter activation. Furthermore, Meox1 protein can bind the same DNA sequences recognized by Hoxa2 on Hoxa2 target genes, placing Meox1 genetically downstream of Hoxa2 in branchial arch morphogenesis.","method":"ChIP (Hoxa2 on Meox1 promoter), promoter reporter assays with binding-site mutations, Meox1/Meox2 double-mutant mouse genetics, DNA-binding assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP, promoter mutagenesis, and genetic epistasis all performed; direct target relationship established with multiple orthogonal methods","pmids":["21245383"],"is_preprint":false},{"year":2018,"finding":"Meox1 transcriptionally activates Gata4 in cardiomyocytes, as demonstrated by promoter-activity assays and ChIP. Meox1 overexpression exacerbates pathological cardiac hypertrophy (familial and pressure-overload models), while knockdown ameliorates it; Gata4 knockdown abolishes these effects, placing Meox1 upstream of Gata4 in pathological hypertrophic remodelling.","method":"Cardiac-specific overexpression and knockdown (mouse models), digital gene expression profiling, promoter luciferase assay, ChIP, Gata4 knockdown rescue","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP + promoter assay + in vivo gain/loss-of-function + epistasis rescue with Gata4 KD; multiple orthogonal methods in one study","pmids":["29155983"],"is_preprint":false},{"year":2021,"finding":"MEOX1 binds to the transcriptional initiation site of CCNB1 (cyclin B1) and suppresses its expression, causing G2-phase cell-cycle arrest and inhibiting NSCLC cell proliferation. CCNB1 overexpression rescues the growth inhibition caused by MEOX1 overexpression, establishing a MEOX1→CCNB1 repression axis in lung cancer cells.","method":"ChIP (MEOX1 on CCNB1 promoter), stable MEOX1 overexpression, in vitro/in vivo proliferation assays, CCNB1 rescue overexpression","journal":"Environmental toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus rescue experiment support direct repression; single lab but two orthogonal methods","pmids":["34837450"],"is_preprint":false},{"year":2020,"finding":"Combined p53- and PTEN-deficiency activates MEOX1 expression in TNBC cells. MEOX1 knockdown in these cells decreases expression of TYK2, STAT5B, and STAT6, abolishes cell proliferation in vitro, and inhibits tumor growth in vivo, indicating MEOX1 is required for growth downstream of combined p53/PTEN loss and upstream of JAK-STAT signalling components.","method":"siRNA double knockdown of p53 and PTEN, MEOX1 siRNA knockdown, RNA-Seq, immunoblotting, in vivo xenograft","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-Seq + immunoblot + in vivo tumor model; single lab but multiple orthogonal readouts","pmids":["32467227"],"is_preprint":false},{"year":2020,"finding":"TGF-β1 transcriptionally upregulates Meox1 in adult human dermal fibroblasts via Smad2 and Smad3, which directly bind the Meox1 promoter as shown by ChIP-qPCR. Meox1 overexpression promotes, and Meox1 knockdown reduces, fibroblast migration in scratch and Transwell assays.","method":"Transcriptome sequencing, RT-PCR, ChIP-qPCR (Smad2/3 on Meox1 promoter), Smad overexpression and siRNA knockdown, scratch/Transwell migration assays","journal":"Zhonghua shao shang za zhi","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR with Smad OE and KD validation plus functional migration assays; single lab, multiple orthogonal methods","pmids":["32241049"],"is_preprint":false},{"year":2024,"finding":"Ailanthone (AIL) suppresses MEOX1 expression by disrupting the interaction between the transcription factor JUN and the MEOX1 promoter, thereby blocking JUN-dependent MEOX1 activation. MEOX1 knockdown inhibits TGF-β1-induced fibroblast activation and endothelial-to-mesenchymal transition in vitro and ameliorates bleomycin-induced pulmonary fibrosis in vivo.","method":"High-throughput small-molecule screening, promoter-binding disruption assay, MEOX1 knockdown in fibroblasts and endothelial cells, bleomycin mouse model, in vitro fibroblast activation assays","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic link between JUN and MEOX1 promoter established with promoter assay; supported by in vitro and in vivo functional data; single lab","pmids":["39220862"],"is_preprint":false},{"year":2024,"finding":"MEOX1 promotes myofibroblast apoptosis resistance in pulmonary fibrosis by transcriptionally upregulating RGS4 (G-protein signaling regulatory factor 4) in TGF-β1-induced myofibroblasts. MEOX1 silencing enhances myofibroblast apoptosis and attenuates fibrosis progression in bleomycin-treated mice.","method":"Bioinformatics target prediction, siRNA-mediated MEOX1 knockdown, in vitro TGF-β1-induced myofibroblast model, apoptosis assays, bleomycin mouse model","journal":"Journal of cellular physiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — downstream target (RGS4) identified by bioinformatics prediction, functional rescue not shown; single lab, limited mechanistic validation","pmids":["39319990"],"is_preprint":false},{"year":2026,"finding":"Meox1 transcriptionally activates Cthrc1 (collagen triple helix repeat containing 1) in cardiac fibroblasts, which promotes Smad2/3 phosphorylation and cardiac fibroblast-to-myofibroblast conversion. Meox1 knockdown attenuates cardiac fibrosis post-MI; Cthrc1 overexpression abolishes this cardioprotection, establishing a Meox1→Cthrc1→p-Smad2/3 signalling axis.","method":"Mouse MI model with Meox1 knockdown, primary cardiac fibroblast gain/loss-of-function, ChIP or promoter analysis for Cthrc1, Smad2/3 phosphorylation assays, Cthrc1 rescue overexpression in vivo and in vitro","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro epistasis with Cthrc1 rescue plus Smad phosphorylation readout; single lab but multiple orthogonal approaches","pmids":["41362745"],"is_preprint":false},{"year":2025,"finding":"MEOX1 directly binds the ABHD3 gene promoter to activate its transcription, thereby driving circABHD3 generation. circABHD3 promotes YTHDF2-dependent m6A-mediated degradation of YPEL3 mRNA, activating β-catenin signalling and exacerbating hepatic fibrosis through EMT and mitochondrial impairment.","method":"Luciferase reporter assay, ChIP (MEOX1 on ABHD3 promoter), methylated RNA immunoprecipitation (MeRIP), RIP and RNA pull-down for circABHD3-YTHDF2 interaction, in vivo CCl4/BDL fibrosis mouse models with knockdown","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP + luciferase for direct promoter binding, multiple downstream interaction assays, in vivo validation; single lab","pmids":["40100806"],"is_preprint":false},{"year":2026,"finding":"MEOX1 binds the TEAD2 promoter (at the -988 to -982 nt region) to activate TEAD2 transcription in hepatic stellate cells, stimulating Hippo signalling target transcription and promoting HSC activation and proliferation. Ligustilide binds the HOX domain of MEOX1 (confirmed by CETSA and SPR), inhibiting its function and alleviating hepatic fibrosis.","method":"ChIP, promoter deletion/mutation assays, CETSA, SPR, siRNA knockdown, in vivo CCl4 mouse model, LX-2 cell functional assays","journal":"British journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding mapped by ChIP+mutation, ligand-MEOX1 interaction confirmed by CETSA+SPR; single lab, multiple orthogonal methods","pmids":["42116734"],"is_preprint":false},{"year":2023,"finding":"MEOX1 is expressed specifically in CD4+ Treg cells at levels comparable to FOXP3, is upregulated by IL-2, and has a permissive epigenetic landscape exclusively in Tregs. MEOX1 knockdown profoundly alters downstream gene expression programs and impairs Treg suppressive capacity, identifying MEOX1 as a FOXP3-dependent Treg transcription factor.","method":"Transcriptomic dataset analysis (48 CD4+ T cell conditions), reverse network engineering, epigenetic analysis, IL-2 stimulation, siRNA knockdown with functional suppression assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with defined functional readout (suppressive capacity) plus epigenetic and transcriptomic data; single lab","pmids":["37559728"],"is_preprint":false},{"year":2021,"finding":"Meox1 regulates SDF-1α expression in vascular smooth muscle cells (VSMCs) via activation of CDC42, and promotes CXCR4 expression in Sca-1+ progenitor cells also through CDC42. Meox1 knockdown abolishes Sca-1+ progenitor cell accumulation and migration into the neointima after vascular injury, and CXCR4 inhibition similarly blocks these effects.","method":"Rat carotid balloon injury model, adenoviral shRNA-mediated Meox1 knockdown, CDC42 inhibitor (ZCL278), CXCR4 inhibitor (AMD3100), immunostaining for PCNA/Meox1, neointima quantification","journal":"Stem cell research & therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, largely correlative with pharmacological inhibitors; mechanistic chain (Meox1→CDC42→SDF-1α→CXCR4) not directly dissected by molecular assays","pmids":["34233723"],"is_preprint":false},{"year":2025,"finding":"TGF-β1 upregulates MEOX1 expression in lung fibroblasts through the NOX4-ROS-Smad pathway. Fibroblast-specific MEOX1 knockdown protects mice from bleomycin-induced pulmonary fibrosis and reduces CTGF expression. In vitro, MEOX1 knockdown abolishes TGF-β1-induced mitophagy deficiency by downregulating CTGF, thereby inhibiting fibroblast senescence and over-activation.","method":"RNA-seq, bleomycin mouse model with AAV-shMEOX1 (fibroblast-specific), NOX4/ROS pathway inhibition, in vitro lung fibroblast assays","journal":"European journal of pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway positioned by pharmacological inhibitors (NOX4/ROS) without direct molecular binding evidence for Smad on MEOX1 promoter; single lab","pmids":["40780596"],"is_preprint":false},{"year":2026,"finding":"In glioblastoma cells, MEOX1 represses PAX1, thereby promoting tumor cell proliferation, migration, and invasion. PAX1 overexpression in GBM cells inhibits Treg differentiation from co-cultured CD4+ T cells, while PAX1 knockdown promotes it, linking the MEOX1→PAX1 repression axis to both intrinsic tumor aggressiveness and immunosuppression in the tumor microenvironment.","method":"GBM cell line gain/loss-of-function, functional proliferation/migration/invasion assays, co-culture CD4+ T cell Treg differentiation assays, PAX1 overexpression rescue","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional evidence in cell lines with rescue, but direct promoter binding of MEOX1 to PAX1 not demonstrated; single lab","pmids":["41692908"],"is_preprint":false},{"year":2026,"finding":"MEOX1 binds the SPHK1 (sphingosine kinase 1) promoter to activate S1P synthesis in ovarian cancer cells, driving a dual autocrine (S1PR3-dependent proliferation/migration) and paracrine (S1P/S1PR1-dependent reprogramming of fibroblasts to VEGF-C-secreting CAFs) program that promotes lymphangiogenesis and lymph node metastasis. SPHK1 inhibition blunts these phenotypes; S1P supplementation restores them.","method":"MEOX1 overexpression in vivo LNM model, spatial transcriptomics, immunostaining, promoter binding assay (MEOX1 on SPHK1 promoter), SPHK1 inhibitor and S1P rescue experiments, CAF-LEC co-culture, 113-patient cohort validation","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter binding plus in vivo rescue/inhibition experiments and spatial transcriptomics; single lab but multiple orthogonal methods","pmids":["42107070"],"is_preprint":false},{"year":2025,"finding":"MEOX1 promotes SERPINE1 transcription in hepatic stellate cells (HSCs), thereby activating HSCs and promoting MASH-related liver fibrosis. MEOX1 knockdown suppresses HSC activation, proliferation, and migration; SERPINE1 was identified as the critical downstream target by RNA-seq.","method":"RNA-seq in MEOX1-knockdown HSCs, in vitro HSC functional assays (activation, proliferation, migration), MASH mouse model, AlphaFold/PyMOL interaction prediction","journal":"The International journal of biological markers","confidence":"Low","confidence_rationale":"Tier 3 / Weak — downstream target identified by RNA-seq without direct ChIP or promoter binding confirmation for MEOX1→SERPINE1; single lab","pmids":["40270091"],"is_preprint":false},{"year":2020,"finding":"PPARα directly regulates MEOX1 expression in cardiomyocytes; PPARα gene delivery reduces cardiac dysfunction and mitochondria-dependent apoptosis in doxorubicin-treated mice, and these cardioprotective effects are abolished by MEOX1 knockdown, placing MEOX1 downstream of PPARα in this cardioprotective pathway.","method":"rAAV9-mediated PPARα delivery in mice, MEOX1 knockdown rescue, cardiac function (echocardiography), apoptosis assays","journal":"Frontiers in pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — MEOX1 positioned downstream of PPARα by knockdown rescue, but direct PPARα-MEOX1 promoter interaction not shown; single lab","pmids":["33132907"],"is_preprint":false}],"current_model":"MEOX1 is a homeodomain transcription factor that directly regulates target gene transcription (including CCNB1/cyclin B1, p16INK4a, p21CIP1/WAF1, Tbx18, Uncx, Bapx1, Gata4, Cthrc1, TEAD2, SPHK1, and ABHD3) to control cell-cycle progression (primarily G2 arrest via CCNB1 repression), somite/sclerotome polarity and axial skeleton formation, haematopoietic stem cell induction through endotomal endothelial cell specification in zebrafish, muscle stem cell self-renewal, endothelial cell senescence, cardiac hypertrophic remodelling, and fibrotic activation in multiple organ contexts; its own transcription is activated by Hoxa2 (in branchial arch development) and by TGF-β1/Smad2-3 signalling."},"narrative":{"mechanistic_narrative":"MEOX1 is a homeodomain transcription factor that controls cell-cycle progression, paraxial mesoderm patterning, and stromal/fibrotic cell-state transitions by directly binding promoters of downstream regulatory genes [PMID:19520072, PMID:34837450]. In the developing somite, MEOX1 directly occupies conserved promoter elements of the transcription factors Tbx18 and Uncx to maintain rostro-caudal sclerotome polarity and axial skeleton identity [PMID:19520072], specifies endotomal endothelial precursors that colonize the dorsal aorta to induce haematopoietic stem cells in zebrafish [PMID:25119043], and enforces a G2 cell-cycle arrest in muscle stem cells by directly repressing cyclin B1 (ccnb1) to prevent premature lineage commitment [PMID:28686860]. This ccnb1/CCNB1-repression mechanism is redeployed in cancer cells, where direct MEOX1 binding at the CCNB1 transcription start site drives G2 arrest and limits proliferation [PMID:34837450]. MEOX1 also imposes G1/S arrest and endothelial senescence through dual modes: DNA-binding-dependent activation of p16INK4a and DNA-binding-independent induction of p21CIP1/WAF1 [PMID:22206000]. Across multiple organs MEOX1 acts as a TGF-β1/Smad-inducible effector of fibrotic and hypertrophic remodelling, transcriptionally activating Gata4 in pathological cardiac hypertrophy [PMID:29155983], Cthrc1 to amplify Smad2/3 phosphorylation in cardiac fibrosis [PMID:41362745], and TEAD2, ABHD3, and SPHK1 in hepatic and tumour stromal programs [PMID:42116734, PMID:40100806, PMID:42107070]; its own promoter is bound and activated by Smad2/3 downstream of TGF-β1 [PMID:32241049] and by JUN [PMID:39220862]. MEOX1 is positioned downstream of Hoxa2 in branchial arch morphogenesis, with Hoxa2 directly activating the Meox1 promoter [PMID:21245383]. MEOX1 additionally functions as a FOXP3-dependent, IL-2-inducible regulatory T cell transcription factor required for Treg suppressive capacity [PMID:37559728].","teleology":[{"year":2009,"claim":"Established that MEOX1 patterns the axial skeleton not by indirect means but through direct transcriptional control of downstream patterning factors, defining its developmental mechanism.","evidence":"Mouse knockout with ChIP for conserved Tbx18/Uncx/Bapx1 promoter elements and proliferation/expression analysis in sclerotome","pmids":["19520072"],"confidence":"High","gaps":["Cofactors mediating activation vs. repression at these promoters not identified","Does not address MEOX1 function outside paraxial mesoderm"]},{"year":2011,"claim":"Resolved how MEOX1 is wired into developmental hierarchies and revealed two mechanistically distinct activation modes, showing transcriptional output is not uniform across targets.","evidence":"ChIP and promoter mutagenesis placing Meox1 downstream of Hoxa2 in branchial arch; DNA-binding-deficient mutants distinguishing p16INK4a (binding-dependent) from p21CIP1/WAF1 (binding-independent) induction in endothelial cells","pmids":["21245383","22206000"],"confidence":"High","gaps":["Mechanism of DNA-binding-independent p21 induction not defined","Identity of partner factors for binding-independent activation unknown"]},{"year":2014,"claim":"Defined a lineage-specifying role for MEOX1 in linking somite-derived endothelium to blood stem cell induction, expanding its function beyond skeletal patterning.","evidence":"Zebrafish loss-of-function genetics, lineage tracing, live imaging, and epistasis with chemokine pathway mutants","pmids":["25119043"],"confidence":"High","gaps":["Direct transcriptional targets driving endotome specification not identified","Conservation of the endotome program in mammals unaddressed"]},{"year":2017,"claim":"Identified the core cell-cycle mechanism by which MEOX1 governs stem cell dynamics: direct repression of cyclin B1 to enforce G2 arrest and preserve self-renewal.","evidence":"Zebrafish genetics, clonal analysis, ccnb1 promoter binding, and ccnb1-overexpression rescue","pmids":["28686860"],"confidence":"High","gaps":["Whether MEOX1 acts as direct repressor or via recruited corepressors not resolved","Signals controlling MEOX1 activity in muscle stem cells unknown"]},{"year":2018,"claim":"Extended MEOX1 transcriptional control to pathological cardiac remodelling by identifying Gata4 as a direct effector target.","evidence":"Cardiac-specific gain/loss-of-function mouse models, promoter luciferase, ChIP, and Gata4-knockdown epistasis rescue","pmids":["29155983"],"confidence":"High","gaps":["Upstream signals activating MEOX1 in hypertrophy not defined here","Whether Gata4 is the sole hypertrophic target unknown"]},{"year":2020,"claim":"Positioned MEOX1 as a TGF-β1/Smad-inducible effector and as a growth driver in tumour contexts, establishing both its upstream regulation and oncogenic role.","evidence":"ChIP-qPCR for Smad2/3 on the Meox1 promoter with Smad OE/KD and migration assays in dermal fibroblasts; siRNA knockdown in p53/PTEN-null TNBC with RNA-seq and xenografts","pmids":["32241049","32467227"],"confidence":"Medium","gaps":["Direct MEOX1 targets in TNBC (TYK2/STAT5B/STAT6) not shown to be directly bound","Single-lab studies"]},{"year":2021,"claim":"Reinforced the conserved MEOX1→CCNB1 repression axis as a cell-cycle control mechanism operative in cancer cells.","evidence":"ChIP for MEOX1 at the CCNB1 TSS, stable overexpression, and CCNB1-rescue proliferation assays in NSCLC","pmids":["34837450"],"confidence":"Medium","gaps":["Repression mechanism (corepressor recruitment) not defined","Single lab"]},{"year":2023,"claim":"Revealed an unanticipated immune role for MEOX1 as a FOXP3-dependent regulatory T cell transcription factor required for suppressive function.","evidence":"Transcriptomic and epigenetic analysis across CD4+ conditions, IL-2 stimulation, and siRNA knockdown with suppression assays","pmids":["37559728"],"confidence":"Medium","gaps":["Direct MEOX1 target genes in Tregs not mapped","Relationship to FOXP3 at the molecular level unresolved"]},{"year":2025,"claim":"Mapped MEOX1 as a central node of multi-organ fibrosis by identifying direct stromal target genes and druggable interfaces.","evidence":"ChIP/luciferase for MEOX1 at ABHD3 and SPHK1 promoters with downstream m6A/S1P axis dissection and in vivo fibrosis/metastasis models; ligand binding to the MEOX1 HOX domain (CETSA/SPR) at the TEAD2 promoter; JUN-MEOX1 promoter disruption by ailanthone","pmids":["40100806","42107070","42116734","39220862"],"confidence":"Medium","gaps":["Whether these stromal targets are co-regulated by a shared cofactor unknown","Direct binding not confirmed for some predicted targets (SERPINE1, RGS4, PAX1)"]},{"year":null,"claim":"It remains unknown what cofactors and chromatin context switch MEOX1 between transcriptional activation and repression at distinct target promoters across development, immunity, and fibrosis.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of MEOX1-DNA-cofactor complexes","No unified explanation for activator vs. repressor behavior","Mechanism of DNA-binding-independent target activation undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,3,5,6,11,13,18]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[2,3,4,6,13]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,3,4]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,3,6]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,4,5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,2,4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[11,12,13,18]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,11]}],"complexes":[],"partners":["HOXA2","SMAD2","SMAD3","JUN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P50221","full_name":"Homeobox protein MOX-1","aliases":["Mesenchyme homeobox 1"],"length_aa":254,"mass_kda":28.0,"function":"Mesodermal transcription factor that plays a key role in somitogenesis and is specifically required for sclerotome development. Required for maintenance of the sclerotome polarity and formation of the cranio-cervical joints (PubMed:23290072, PubMed:24073994). Binds specifically to the promoter of target genes and regulates their expression. Activates expression of NKX3-2 in the sclerotome. Activates expression of CDKN1A and CDKN2A in endothelial cells, acting as a regulator of vascular cell proliferation. While it activates CDKN1A in a DNA-dependent manner, it activates CDKN2A in a DNA-independent manner. Required for hematopoietic stem cell (HSCs) induction via its role in somitogenesis: specification of HSCs occurs via the deployment of a specific endothelial precursor population, which arises within a sub-compartment of the somite named endotome","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P50221/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MEOX1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MEOX1","total_profiled":1310},"omim":[{"mim_id":"608022","title":"DIAPHANOSPONDYLODYSOSTOSIS","url":"https://www.omim.org/entry/608022"},{"mim_id":"600147","title":"MESENCHYME HOMEOBOX 1; MEOX1","url":"https://www.omim.org/entry/600147"},{"mim_id":"239100","title":"VAN BUCHEM DISEASE; VBCH","url":"https://www.omim.org/entry/239100"},{"mim_id":"214300","title":"KLIPPEL-FEIL SYNDROME 2, AUTOSOMAL RECESSIVE; KFS2","url":"https://www.omim.org/entry/214300"},{"mim_id":"161000","title":"NAEGELI-FRANCESCHETTI-JADASSOHN SYNDROME; NFJS","url":"https://www.omim.org/entry/161000"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytokinetic bridge","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose tissue","ntpm":31.3},{"tissue":"breast","ntpm":22.5},{"tissue":"heart muscle","ntpm":22.4}],"url":"https://www.proteinatlas.org/search/MEOX1"},"hgnc":{"alias_symbol":["MOX1"],"prev_symbol":[]},"alphafold":{"accession":"P50221","domains":[{"cath_id":"1.10.10.60","chopping":"181-231","consensus_level":"high","plddt":96.6927,"start":181,"end":231}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P50221","model_url":"https://alphafold.ebi.ac.uk/files/AF-P50221-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P50221-F1-predicted_aligned_error_v6.png","plddt_mean":62.53},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MEOX1","jax_strain_url":"https://www.jax.org/strain/search?query=MEOX1"},"sequence":{"accession":"P50221","fasta_url":"https://rest.uniprot.org/uniprotkb/P50221.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P50221/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P50221"}},"corpus_meta":[{"pmid":"12116252","id":"PMC_12116252","title":"A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population.","date":"2002","source":"American journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12116252","citation_count":241,"is_preprint":false},{"pmid":"25119043","id":"PMC_25119043","title":"Haematopoietic stem cell induction by somite-derived endothelial cells controlled by meox1.","date":"2014","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/25119043","citation_count":127,"is_preprint":false},{"pmid":"28686860","id":"PMC_28686860","title":"Muscle Stem Cells Undergo Extensive Clonal Drift during Tissue Growth via Meox1-Mediated Induction of G2 Cell-Cycle Arrest.","date":"2017","source":"Cell stem cell","url":"https://pubmed.ncbi.nlm.nih.gov/28686860","citation_count":67,"is_preprint":false},{"pmid":"23290072","id":"PMC_23290072","title":"Mutations in MEOX1, encoding mesenchyme homeobox 1, cause Klippel-Feil anomaly.","date":"2013","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23290072","citation_count":63,"is_preprint":false},{"pmid":"22206000","id":"PMC_22206000","title":"Mechanisms of MEOX1 and MEOX2 regulation of the cyclin dependent kinase inhibitors p21 and p16 in vascular endothelial cells.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22206000","citation_count":60,"is_preprint":false},{"pmid":"24073994","id":"PMC_24073994","title":"Mutation in MEOX1 gene causes a recessive Klippel-Feil syndrome subtype.","date":"2013","source":"BMC genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24073994","citation_count":48,"is_preprint":false},{"pmid":"19520072","id":"PMC_19520072","title":"Lack of the mesodermal homeodomain protein MEOX1 disrupts sclerotome polarity and leads to a remodeling of the cranio-cervical joints of the axial skeleton.","date":"2009","source":"Developmental 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radiopharmaceuticals","url":"https://pubmed.ncbi.nlm.nih.gov/30543460","citation_count":4,"is_preprint":false},{"pmid":"29204471","id":"PMC_29204471","title":"Data on the involvement of Meox1 in balloon-injury-induced neointima formation of rats.","date":"2017","source":"Data in brief","url":"https://pubmed.ncbi.nlm.nih.gov/29204471","citation_count":4,"is_preprint":false},{"pmid":"37559728","id":"PMC_37559728","title":"Identification of the novel FOXP3-dependent Treg cell transcription factor MEOX1 by high-dimensional analysis of human CD4+ T cells.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37559728","citation_count":4,"is_preprint":false},{"pmid":"32241049","id":"PMC_32241049","title":"[Mechanism of transcriptional regulation of Meox1 by transforming growth factor β (1) and its effect on cell migration of adult human dermal fibroblasts].","date":"2020","source":"Zhonghua shao shang za zhi = Zhonghua shaoshang zazhi = Chinese journal of burns","url":"https://pubmed.ncbi.nlm.nih.gov/32241049","citation_count":3,"is_preprint":false},{"pmid":"41362745","id":"PMC_41362745","title":"Meox1 Promotes Cardiac Fibrosis and Pathological Remodeling following Myocardial Infarction through Cthrc1/p-Smad2/3 Signaling.","date":"2026","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41362745","citation_count":1,"is_preprint":false},{"pmid":"40919531","id":"PMC_40919531","title":"Organelle stresses and energetic metabolisms promote endothelial-to-mesenchymal transition and fibrosis via upregulating FOSB and MEOX1 in Alzheimer's disease.","date":"2025","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/40919531","citation_count":1,"is_preprint":false},{"pmid":"38732090","id":"PMC_38732090","title":"Regulatory Role of Meox1 in Muscle Growth of Sebastes schlegelii.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38732090","citation_count":1,"is_preprint":false},{"pmid":"40100806","id":"PMC_40100806","title":"MEOX1-mediated transcriptional regulation of circABHD3 exacerbates hepatic fibrosis through promoting m6A/YTHDF2-dependent YPEL3 mRNA decay to activate β-catenin signaling.","date":"2025","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40100806","citation_count":1,"is_preprint":false},{"pmid":"36138442","id":"PMC_36138442","title":"The squiggle tail (squig) mutation in mice is associated with a deletion in the mesenchyme homeobox 1 (Meox1) gene.","date":"2022","source":"BMC research notes","url":"https://pubmed.ncbi.nlm.nih.gov/36138442","citation_count":1,"is_preprint":false},{"pmid":"41612494","id":"PMC_41612494","title":"DNA methylation-mediated silencing of MEOX1 promotes glycolysis and immune evasion in colorectal cancer cells through inhibition of GLP2R transcription.","date":"2026","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/41612494","citation_count":1,"is_preprint":false},{"pmid":"40780596","id":"PMC_40780596","title":"Transcription factor MEOX1 accelerates pulmonary fibrosis by regulating mitophagy and senescence.","date":"2025","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40780596","citation_count":0,"is_preprint":false},{"pmid":"40270091","id":"PMC_40270091","title":"Identification of MEOX1 as a potential target in metabolic dysfunction-associated steatohepatitis-related liver fibrosis.","date":"2025","source":"The International journal of biological markers","url":"https://pubmed.ncbi.nlm.nih.gov/40270091","citation_count":0,"is_preprint":false},{"pmid":"42002886","id":"PMC_42002886","title":"Meox1 promotes hepatocellular carcinoma progression potentially via regulation of cell cycle and p21 expression.","date":"2026","source":"Cell adhesion & 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fibrosis","date":"2025-07-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.09.663937","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23674,"output_tokens":6063,"usd":0.080983,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14796,"output_tokens":3582,"usd":0.081765,"stage2_stop_reason":"end_turn"},"total_usd":0.162748,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"In zebrafish, meox1 specifies endotomal endothelial precursor cells within a sub-compartment of the nascent somite (the endotome); these cells migrate to colonize the dorsal aorta and induce haematopoietic stem cell formation via chemokine signalling. Loss of meox1 expands the endotome at the expense of muscle precursors (external cell layer), generating excess endotome-derived cells in the dorsal aorta and a dramatic increase in HSC induction.\",\n      \"method\": \"Zebrafish loss-of-function genetics, lineage tracing, live imaging, epistasis with chemokine pathway mutants\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetics, lineage tracing, live imaging, epistasis) in a high-profile publication; findings mechanistically link meox1 to endotome specification and HSC induction pathway\",\n      \"pmids\": [\"25119043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Meox1 directly inhibits the cell-cycle checkpoint gene ccnb1 (cyclin B1), thereby initiating G2 cell-cycle arrest within muscle stem cells. Disrupting this G2 arrest causes premature lineage commitment and defects in muscle growth. This establishes a Meox1→ccnb1 repression axis governing muscle stem cell dynamics during zebrafish myotome growth.\",\n      \"method\": \"Zebrafish genetics, clonal analysis, chromatin binding assays (direct inhibition of ccnb1 promoter), rescue experiments with ccnb1 overexpression\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding to ccnb1 promoter demonstrated, zebrafish genetic loss-of-function with defined cellular phenotype, rescue experiments; independently corroborated in Sebastes schlegelii (PMID:38732090)\",\n      \"pmids\": [\"28686860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Meox1 occupies conserved promoter regions of the transcription factor genes Tbx18 and Uncx (as well as the previously known target Bapx1) in the sclerotome, as shown by chromatin immunoprecipitation. Loss of Meox1 in mice alters relative cell proliferation rates in the rostral vs. caudal sclerotome, disrupts rostro-caudal polarity, and causes atlas-to-basioccipital assimilation—demonstrating a non-redundant role for Meox1 in maintaining sclerotome polarity through direct transcriptional regulation of downstream transcription factors.\",\n      \"method\": \"Mouse homozygous knockout, chromatin immunoprecipitation (ChIP) for conserved promoter elements, proliferation assays, gene expression analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP for direct promoter occupancy combined with mouse KO phenotypic analysis and expression studies, rigorous mechanistic dissection in a focused study\",\n      \"pmids\": [\"19520072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MEOX1 (and MEOX2) activate p16(INK4a) expression in a DNA-binding-dependent manner, whereas they induce p21(CIP1/WAF1) in a DNA-binding-independent manner, both leading to G1/S cell-cycle arrest and endothelial cell senescence. This demonstrates mechanistically distinct modes of transcriptional activation for two CDK inhibitor target genes.\",\n      \"method\": \"Overexpression of wild-type vs. DNA-binding-deficient MEOX1/MEOX2 mutants in vascular endothelial cells; cell cycle and senescence assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site/DNA-binding mutagenesis with functional readout (cell cycle arrest, senescence), two orthogonal mechanistic conclusions from same study\",\n      \"pmids\": [\"22206000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Meox1 is a direct transcriptional target of Hoxa2 in the second branchial arch: Hoxa2 binds two conserved sites in the Meox1 proximal promoter by ChIP, and these sites are required for Hoxa2-dependent Meox1 promoter activation. Furthermore, Meox1 protein can bind the same DNA sequences recognized by Hoxa2 on Hoxa2 target genes, placing Meox1 genetically downstream of Hoxa2 in branchial arch morphogenesis.\",\n      \"method\": \"ChIP (Hoxa2 on Meox1 promoter), promoter reporter assays with binding-site mutations, Meox1/Meox2 double-mutant mouse genetics, DNA-binding assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP, promoter mutagenesis, and genetic epistasis all performed; direct target relationship established with multiple orthogonal methods\",\n      \"pmids\": [\"21245383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Meox1 transcriptionally activates Gata4 in cardiomyocytes, as demonstrated by promoter-activity assays and ChIP. Meox1 overexpression exacerbates pathological cardiac hypertrophy (familial and pressure-overload models), while knockdown ameliorates it; Gata4 knockdown abolishes these effects, placing Meox1 upstream of Gata4 in pathological hypertrophic remodelling.\",\n      \"method\": \"Cardiac-specific overexpression and knockdown (mouse models), digital gene expression profiling, promoter luciferase assay, ChIP, Gata4 knockdown rescue\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP + promoter assay + in vivo gain/loss-of-function + epistasis rescue with Gata4 KD; multiple orthogonal methods in one study\",\n      \"pmids\": [\"29155983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MEOX1 binds to the transcriptional initiation site of CCNB1 (cyclin B1) and suppresses its expression, causing G2-phase cell-cycle arrest and inhibiting NSCLC cell proliferation. CCNB1 overexpression rescues the growth inhibition caused by MEOX1 overexpression, establishing a MEOX1→CCNB1 repression axis in lung cancer cells.\",\n      \"method\": \"ChIP (MEOX1 on CCNB1 promoter), stable MEOX1 overexpression, in vitro/in vivo proliferation assays, CCNB1 rescue overexpression\",\n      \"journal\": \"Environmental toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus rescue experiment support direct repression; single lab but two orthogonal methods\",\n      \"pmids\": [\"34837450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Combined p53- and PTEN-deficiency activates MEOX1 expression in TNBC cells. MEOX1 knockdown in these cells decreases expression of TYK2, STAT5B, and STAT6, abolishes cell proliferation in vitro, and inhibits tumor growth in vivo, indicating MEOX1 is required for growth downstream of combined p53/PTEN loss and upstream of JAK-STAT signalling components.\",\n      \"method\": \"siRNA double knockdown of p53 and PTEN, MEOX1 siRNA knockdown, RNA-Seq, immunoblotting, in vivo xenograft\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-Seq + immunoblot + in vivo tumor model; single lab but multiple orthogonal readouts\",\n      \"pmids\": [\"32467227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TGF-β1 transcriptionally upregulates Meox1 in adult human dermal fibroblasts via Smad2 and Smad3, which directly bind the Meox1 promoter as shown by ChIP-qPCR. Meox1 overexpression promotes, and Meox1 knockdown reduces, fibroblast migration in scratch and Transwell assays.\",\n      \"method\": \"Transcriptome sequencing, RT-PCR, ChIP-qPCR (Smad2/3 on Meox1 promoter), Smad overexpression and siRNA knockdown, scratch/Transwell migration assays\",\n      \"journal\": \"Zhonghua shao shang za zhi\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR with Smad OE and KD validation plus functional migration assays; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"32241049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Ailanthone (AIL) suppresses MEOX1 expression by disrupting the interaction between the transcription factor JUN and the MEOX1 promoter, thereby blocking JUN-dependent MEOX1 activation. MEOX1 knockdown inhibits TGF-β1-induced fibroblast activation and endothelial-to-mesenchymal transition in vitro and ameliorates bleomycin-induced pulmonary fibrosis in vivo.\",\n      \"method\": \"High-throughput small-molecule screening, promoter-binding disruption assay, MEOX1 knockdown in fibroblasts and endothelial cells, bleomycin mouse model, in vitro fibroblast activation assays\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic link between JUN and MEOX1 promoter established with promoter assay; supported by in vitro and in vivo functional data; single lab\",\n      \"pmids\": [\"39220862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MEOX1 promotes myofibroblast apoptosis resistance in pulmonary fibrosis by transcriptionally upregulating RGS4 (G-protein signaling regulatory factor 4) in TGF-β1-induced myofibroblasts. MEOX1 silencing enhances myofibroblast apoptosis and attenuates fibrosis progression in bleomycin-treated mice.\",\n      \"method\": \"Bioinformatics target prediction, siRNA-mediated MEOX1 knockdown, in vitro TGF-β1-induced myofibroblast model, apoptosis assays, bleomycin mouse model\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — downstream target (RGS4) identified by bioinformatics prediction, functional rescue not shown; single lab, limited mechanistic validation\",\n      \"pmids\": [\"39319990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Meox1 transcriptionally activates Cthrc1 (collagen triple helix repeat containing 1) in cardiac fibroblasts, which promotes Smad2/3 phosphorylation and cardiac fibroblast-to-myofibroblast conversion. Meox1 knockdown attenuates cardiac fibrosis post-MI; Cthrc1 overexpression abolishes this cardioprotection, establishing a Meox1→Cthrc1→p-Smad2/3 signalling axis.\",\n      \"method\": \"Mouse MI model with Meox1 knockdown, primary cardiac fibroblast gain/loss-of-function, ChIP or promoter analysis for Cthrc1, Smad2/3 phosphorylation assays, Cthrc1 rescue overexpression in vivo and in vitro\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro epistasis with Cthrc1 rescue plus Smad phosphorylation readout; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"41362745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MEOX1 directly binds the ABHD3 gene promoter to activate its transcription, thereby driving circABHD3 generation. circABHD3 promotes YTHDF2-dependent m6A-mediated degradation of YPEL3 mRNA, activating β-catenin signalling and exacerbating hepatic fibrosis through EMT and mitochondrial impairment.\",\n      \"method\": \"Luciferase reporter assay, ChIP (MEOX1 on ABHD3 promoter), methylated RNA immunoprecipitation (MeRIP), RIP and RNA pull-down for circABHD3-YTHDF2 interaction, in vivo CCl4/BDL fibrosis mouse models with knockdown\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP + luciferase for direct promoter binding, multiple downstream interaction assays, in vivo validation; single lab\",\n      \"pmids\": [\"40100806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MEOX1 binds the TEAD2 promoter (at the -988 to -982 nt region) to activate TEAD2 transcription in hepatic stellate cells, stimulating Hippo signalling target transcription and promoting HSC activation and proliferation. Ligustilide binds the HOX domain of MEOX1 (confirmed by CETSA and SPR), inhibiting its function and alleviating hepatic fibrosis.\",\n      \"method\": \"ChIP, promoter deletion/mutation assays, CETSA, SPR, siRNA knockdown, in vivo CCl4 mouse model, LX-2 cell functional assays\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding mapped by ChIP+mutation, ligand-MEOX1 interaction confirmed by CETSA+SPR; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"42116734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MEOX1 is expressed specifically in CD4+ Treg cells at levels comparable to FOXP3, is upregulated by IL-2, and has a permissive epigenetic landscape exclusively in Tregs. MEOX1 knockdown profoundly alters downstream gene expression programs and impairs Treg suppressive capacity, identifying MEOX1 as a FOXP3-dependent Treg transcription factor.\",\n      \"method\": \"Transcriptomic dataset analysis (48 CD4+ T cell conditions), reverse network engineering, epigenetic analysis, IL-2 stimulation, siRNA knockdown with functional suppression assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with defined functional readout (suppressive capacity) plus epigenetic and transcriptomic data; single lab\",\n      \"pmids\": [\"37559728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Meox1 regulates SDF-1α expression in vascular smooth muscle cells (VSMCs) via activation of CDC42, and promotes CXCR4 expression in Sca-1+ progenitor cells also through CDC42. Meox1 knockdown abolishes Sca-1+ progenitor cell accumulation and migration into the neointima after vascular injury, and CXCR4 inhibition similarly blocks these effects.\",\n      \"method\": \"Rat carotid balloon injury model, adenoviral shRNA-mediated Meox1 knockdown, CDC42 inhibitor (ZCL278), CXCR4 inhibitor (AMD3100), immunostaining for PCNA/Meox1, neointima quantification\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, largely correlative with pharmacological inhibitors; mechanistic chain (Meox1→CDC42→SDF-1α→CXCR4) not directly dissected by molecular assays\",\n      \"pmids\": [\"34233723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TGF-β1 upregulates MEOX1 expression in lung fibroblasts through the NOX4-ROS-Smad pathway. Fibroblast-specific MEOX1 knockdown protects mice from bleomycin-induced pulmonary fibrosis and reduces CTGF expression. In vitro, MEOX1 knockdown abolishes TGF-β1-induced mitophagy deficiency by downregulating CTGF, thereby inhibiting fibroblast senescence and over-activation.\",\n      \"method\": \"RNA-seq, bleomycin mouse model with AAV-shMEOX1 (fibroblast-specific), NOX4/ROS pathway inhibition, in vitro lung fibroblast assays\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway positioned by pharmacological inhibitors (NOX4/ROS) without direct molecular binding evidence for Smad on MEOX1 promoter; single lab\",\n      \"pmids\": [\"40780596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In glioblastoma cells, MEOX1 represses PAX1, thereby promoting tumor cell proliferation, migration, and invasion. PAX1 overexpression in GBM cells inhibits Treg differentiation from co-cultured CD4+ T cells, while PAX1 knockdown promotes it, linking the MEOX1→PAX1 repression axis to both intrinsic tumor aggressiveness and immunosuppression in the tumor microenvironment.\",\n      \"method\": \"GBM cell line gain/loss-of-function, functional proliferation/migration/invasion assays, co-culture CD4+ T cell Treg differentiation assays, PAX1 overexpression rescue\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional evidence in cell lines with rescue, but direct promoter binding of MEOX1 to PAX1 not demonstrated; single lab\",\n      \"pmids\": [\"41692908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MEOX1 binds the SPHK1 (sphingosine kinase 1) promoter to activate S1P synthesis in ovarian cancer cells, driving a dual autocrine (S1PR3-dependent proliferation/migration) and paracrine (S1P/S1PR1-dependent reprogramming of fibroblasts to VEGF-C-secreting CAFs) program that promotes lymphangiogenesis and lymph node metastasis. SPHK1 inhibition blunts these phenotypes; S1P supplementation restores them.\",\n      \"method\": \"MEOX1 overexpression in vivo LNM model, spatial transcriptomics, immunostaining, promoter binding assay (MEOX1 on SPHK1 promoter), SPHK1 inhibitor and S1P rescue experiments, CAF-LEC co-culture, 113-patient cohort validation\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter binding plus in vivo rescue/inhibition experiments and spatial transcriptomics; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"42107070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MEOX1 promotes SERPINE1 transcription in hepatic stellate cells (HSCs), thereby activating HSCs and promoting MASH-related liver fibrosis. MEOX1 knockdown suppresses HSC activation, proliferation, and migration; SERPINE1 was identified as the critical downstream target by RNA-seq.\",\n      \"method\": \"RNA-seq in MEOX1-knockdown HSCs, in vitro HSC functional assays (activation, proliferation, migration), MASH mouse model, AlphaFold/PyMOL interaction prediction\",\n      \"journal\": \"The International journal of biological markers\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — downstream target identified by RNA-seq without direct ChIP or promoter binding confirmation for MEOX1→SERPINE1; single lab\",\n      \"pmids\": [\"40270091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PPARα directly regulates MEOX1 expression in cardiomyocytes; PPARα gene delivery reduces cardiac dysfunction and mitochondria-dependent apoptosis in doxorubicin-treated mice, and these cardioprotective effects are abolished by MEOX1 knockdown, placing MEOX1 downstream of PPARα in this cardioprotective pathway.\",\n      \"method\": \"rAAV9-mediated PPARα delivery in mice, MEOX1 knockdown rescue, cardiac function (echocardiography), apoptosis assays\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — MEOX1 positioned downstream of PPARα by knockdown rescue, but direct PPARα-MEOX1 promoter interaction not shown; single lab\",\n      \"pmids\": [\"33132907\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MEOX1 is a homeodomain transcription factor that directly regulates target gene transcription (including CCNB1/cyclin B1, p16INK4a, p21CIP1/WAF1, Tbx18, Uncx, Bapx1, Gata4, Cthrc1, TEAD2, SPHK1, and ABHD3) to control cell-cycle progression (primarily G2 arrest via CCNB1 repression), somite/sclerotome polarity and axial skeleton formation, haematopoietic stem cell induction through endotomal endothelial cell specification in zebrafish, muscle stem cell self-renewal, endothelial cell senescence, cardiac hypertrophic remodelling, and fibrotic activation in multiple organ contexts; its own transcription is activated by Hoxa2 (in branchial arch development) and by TGF-β1/Smad2-3 signalling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MEOX1 is a homeodomain transcription factor that controls cell-cycle progression, paraxial mesoderm patterning, and stromal/fibrotic cell-state transitions by directly binding promoters of downstream regulatory genes [#2, #6]. In the developing somite, MEOX1 directly occupies conserved promoter elements of the transcription factors Tbx18 and Uncx to maintain rostro-caudal sclerotome polarity and axial skeleton identity [#2], specifies endotomal endothelial precursors that colonize the dorsal aorta to induce haematopoietic stem cells in zebrafish [#0], and enforces a G2 cell-cycle arrest in muscle stem cells by directly repressing cyclin B1 (ccnb1) to prevent premature lineage commitment [#1]. This ccnb1/CCNB1-repression mechanism is redeployed in cancer cells, where direct MEOX1 binding at the CCNB1 transcription start site drives G2 arrest and limits proliferation [#6]. MEOX1 also imposes G1/S arrest and endothelial senescence through dual modes: DNA-binding-dependent activation of p16INK4a and DNA-binding-independent induction of p21CIP1/WAF1 [#3]. Across multiple organs MEOX1 acts as a TGF-\\u03b21/Smad-inducible effector of fibrotic and hypertrophic remodelling, transcriptionally activating Gata4 in pathological cardiac hypertrophy [#5], Cthrc1 to amplify Smad2/3 phosphorylation in cardiac fibrosis [#11], and TEAD2, ABHD3, and SPHK1 in hepatic and tumour stromal programs [#13, #12, #18]; its own promoter is bound and activated by Smad2/3 downstream of TGF-\\u03b21 [#8] and by JUN [#9]. MEOX1 is positioned downstream of Hoxa2 in branchial arch morphogenesis, with Hoxa2 directly activating the Meox1 promoter [#4]. MEOX1 additionally functions as a FOXP3-dependent, IL-2-inducible regulatory T cell transcription factor required for Treg suppressive capacity [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established that MEOX1 patterns the axial skeleton not by indirect means but through direct transcriptional control of downstream patterning factors, defining its developmental mechanism.\",\n      \"evidence\": \"Mouse knockout with ChIP for conserved Tbx18/Uncx/Bapx1 promoter elements and proliferation/expression analysis in sclerotome\",\n      \"pmids\": [\"19520072\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactors mediating activation vs. repression at these promoters not identified\", \"Does not address MEOX1 function outside paraxial mesoderm\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved how MEOX1 is wired into developmental hierarchies and revealed two mechanistically distinct activation modes, showing transcriptional output is not uniform across targets.\",\n      \"evidence\": \"ChIP and promoter mutagenesis placing Meox1 downstream of Hoxa2 in branchial arch; DNA-binding-deficient mutants distinguishing p16INK4a (binding-dependent) from p21CIP1/WAF1 (binding-independent) induction in endothelial cells\",\n      \"pmids\": [\"21245383\", \"22206000\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of DNA-binding-independent p21 induction not defined\", \"Identity of partner factors for binding-independent activation unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined a lineage-specifying role for MEOX1 in linking somite-derived endothelium to blood stem cell induction, expanding its function beyond skeletal patterning.\",\n      \"evidence\": \"Zebrafish loss-of-function genetics, lineage tracing, live imaging, and epistasis with chemokine pathway mutants\",\n      \"pmids\": [\"25119043\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets driving endotome specification not identified\", \"Conservation of the endotome program in mammals unaddressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified the core cell-cycle mechanism by which MEOX1 governs stem cell dynamics: direct repression of cyclin B1 to enforce G2 arrest and preserve self-renewal.\",\n      \"evidence\": \"Zebrafish genetics, clonal analysis, ccnb1 promoter binding, and ccnb1-overexpression rescue\",\n      \"pmids\": [\"28686860\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MEOX1 acts as direct repressor or via recruited corepressors not resolved\", \"Signals controlling MEOX1 activity in muscle stem cells unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended MEOX1 transcriptional control to pathological cardiac remodelling by identifying Gata4 as a direct effector target.\",\n      \"evidence\": \"Cardiac-specific gain/loss-of-function mouse models, promoter luciferase, ChIP, and Gata4-knockdown epistasis rescue\",\n      \"pmids\": [\"29155983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals activating MEOX1 in hypertrophy not defined here\", \"Whether Gata4 is the sole hypertrophic target unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Positioned MEOX1 as a TGF-\\u03b21/Smad-inducible effector and as a growth driver in tumour contexts, establishing both its upstream regulation and oncogenic role.\",\n      \"evidence\": \"ChIP-qPCR for Smad2/3 on the Meox1 promoter with Smad OE/KD and migration assays in dermal fibroblasts; siRNA knockdown in p53/PTEN-null TNBC with RNA-seq and xenografts\",\n      \"pmids\": [\"32241049\", \"32467227\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MEOX1 targets in TNBC (TYK2/STAT5B/STAT6) not shown to be directly bound\", \"Single-lab studies\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reinforced the conserved MEOX1\\u2192CCNB1 repression axis as a cell-cycle control mechanism operative in cancer cells.\",\n      \"evidence\": \"ChIP for MEOX1 at the CCNB1 TSS, stable overexpression, and CCNB1-rescue proliferation assays in NSCLC\",\n      \"pmids\": [\"34837450\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Repression mechanism (corepressor recruitment) not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed an unanticipated immune role for MEOX1 as a FOXP3-dependent regulatory T cell transcription factor required for suppressive function.\",\n      \"evidence\": \"Transcriptomic and epigenetic analysis across CD4+ conditions, IL-2 stimulation, and siRNA knockdown with suppression assays\",\n      \"pmids\": [\"37559728\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MEOX1 target genes in Tregs not mapped\", \"Relationship to FOXP3 at the molecular level unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mapped MEOX1 as a central node of multi-organ fibrosis by identifying direct stromal target genes and druggable interfaces.\",\n      \"evidence\": \"ChIP/luciferase for MEOX1 at ABHD3 and SPHK1 promoters with downstream m6A/S1P axis dissection and in vivo fibrosis/metastasis models; ligand binding to the MEOX1 HOX domain (CETSA/SPR) at the TEAD2 promoter; JUN-MEOX1 promoter disruption by ailanthone\",\n      \"pmids\": [\"40100806\", \"42107070\", \"42116734\", \"39220862\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these stromal targets are co-regulated by a shared cofactor unknown\", \"Direct binding not confirmed for some predicted targets (SERPINE1, RGS4, PAX1)\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown what cofactors and chromatin context switch MEOX1 between transcriptional activation and repression at distinct target promoters across development, immunity, and fibrosis.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of MEOX1-DNA-cofactor complexes\", \"No unified explanation for activator vs. repressor behavior\", \"Mechanism of DNA-binding-independent target activation undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 3, 5, 6, 11, 13, 18]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [2, 3, 4, 6, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 3, 6]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 4, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [11, 12, 13, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HOXA2\", \"SMAD2\", \"SMAD3\", \"JUN\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}