{"gene":"HOXA6","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1994,"finding":"Targeted disruption of hoxa-6 in mice results in homeotic posterior transformation of the seventh cervical vertebra to the first thoracic vertebra, demonstrating Hoxa-6 is required for axial skeletal identity specification at positions approximating the anterior border of its expression domain in the prevertebrae.","method":"Gene targeting/knockout in mice with skeletal phenotype analysis","journal":"Mechanisms of development","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined skeletal phenotype, replicated with Hoxa-4 in same study","pmids":["7918106"],"is_preprint":false},{"year":2011,"finding":"The lncRNA Mistral (Mira), encoded in the spacer DNA between Hoxa6 and Hoxa7, activates Hoxa6 and Hoxa7 transcription by recruiting the epigenetic activator MLL1 to chromatin, inducing dynamic changes in chromosome conformation.","method":"RNA immunoprecipitation, chromatin conformation capture, lncRNA knockdown and overexpression, MLL1 ChIP in mouse embryonic stem cells","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (RIP, 3C, ChIP, KD/OE) in single study with rigorous controls","pmids":["21925392"],"is_preprint":false},{"year":2009,"finding":"Enforced overexpression of HOXA6 in hematopoietic FDCP-Mix progenitor cells increases proliferation, colony formation, and potentiates factor-independent proliferation in Ba/F3 cells, demonstrating a direct role for HOXA6 in hematopoietic progenitor cell self-renewal and proliferation.","method":"Retroviral overexpression, colony formation assay, growth factor withdrawal assay in primary and cell line hematopoietic progenitors","journal":"Experimental hematology","confidence":"Medium","confidence_rationale":"Tier 2 — clean gain-of-function with defined proliferative phenotype, single lab","pmids":["19157684"],"is_preprint":false},{"year":2021,"finding":"HOXA6 physically interacts with and stabilizes the PBX2 protein in gastric cancer cells; HOXA6 and PBX2 cooperate to promote cell migration, invasion, and metastasis in vitro and in vivo.","method":"Co-immunoprecipitation, STRING database interaction prediction, siRNA knockdown, orthotopic implantation in vivo","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP demonstrating physical interaction, supported by in vitro and in vivo functional assays, single lab","pmids":["33535170"],"is_preprint":false},{"year":2019,"finding":"HOXA6 overexpression in clear cell renal cell carcinoma cells inhibits proliferation and induces apoptosis by suppressing the PI3K/Akt/ERK signaling pathway, reducing p-Akt, p-ERK and Bcl-2 levels while increasing PTEN, Bax and cleaved caspase-3.","method":"Plasmid overexpression and shRNA knockdown, Western blotting, flow cytometry, CCK-8 assay in 786-O and 769-P ccRCC cell lines","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 — loss- and gain-of-function with pathway-level western blot readouts, single lab","pmids":["31081053"],"is_preprint":false},{"year":2018,"finding":"HOXA6 promotes colorectal cancer cell proliferation, migration, and invasion while inhibiting apoptosis; it regulates apoptosis through the Bcl-2 pathway and promotes migration/invasion through induction of epithelial-mesenchymal transition (suppressing E-cadherin, upregulating N-cadherin and Vimentin).","method":"Plasmid overexpression and siRNA knockdown, CCK-8, colony formation, TUNEL, Transwell, wound-healing assays, Western blotting in Caco2 and HT-29 cells","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 — bidirectional manipulation with multiple phenotypic and molecular readouts, single lab","pmids":["29620285"],"is_preprint":false},{"year":2020,"finding":"HOXA6 is upregulated in the spinal dorsal horn following oxaliplatin treatment downstream of SOX10: TET1-mediated demethylation of the SOX10 promoter leads to SOX10 upregulation, which then binds the HOXA6 promoter to drive HOXA6 transcription, contributing to mechanical allodynia.","method":"siRNA knockdown, reduced representation bisulfite sequencing, chromatin immunoprecipitation, AAV overexpression, behavioral pain assays in rat model","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP confirming SOX10 binding to HOXA6 promoter, bisulfite sequencing, multiple genetic interventions, single lab","pmids":["32428246"],"is_preprint":false},{"year":2023,"finding":"HOXA6 transcriptionally activates ZBTB12 by binding to its promoter in gastric cancer-associated fibroblasts (CAFs), and this HOXA6-ZBTB12 axis promotes gastric cancer cell growth, migration, and invasiveness.","method":"ChIP assay confirming HOXA6 binding to ZBTB12 promoter, siRNA knockdown, luciferase reporter assay in 293T cells and CAFs","journal":"Acta pharmaceutica (Zagreb, Croatia)","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP confirming direct promoter binding, supported by functional KD experiments, single lab","pmids":["37708965"],"is_preprint":false},{"year":2025,"finding":"DDR1 promotes bladder cancer progression by targeting HOXA6 to inhibit ferroptosis; DDR1 knockdown-induced ferroptosis was rescued by HOXA6 knockdown, placing HOXA6 downstream of DDR1 in a pathway that maintains GSH, GPX4, and SLC7A11 levels and suppresses lipid peroxidation.","method":"siRNA knockdown, in vitro and in vivo functional assays, Western blotting for ferroptosis markers in bladder cancer cells","journal":"Journal of cellular and molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 — epistasis by double knockdown with defined ferroptosis markers, single lab, single study","pmids":["40105492"],"is_preprint":false},{"year":2024,"finding":"Hoxa6 is differentially expressed in enteric neuronal lineages during enteric nervous system development; in Sox10Dom/+ Hirschsprung mouse mutants, Hoxa6 expression is altered in early developing neurons, implicating Hoxa6 in enteric neuron lineage allocation downstream of Sox10.","method":"Single-cell RNA sequencing, hybridization chain reaction (HCR) validation, gene regulatory network analysis in Sox10Dom/+ mouse ENS","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — associative scRNA-seq with HCR validation but no direct loss-of-function for Hoxa6; preprint","pmids":["39345473"],"is_preprint":true},{"year":2025,"finding":"KIAA1429 (VIRMA) promotes NSCLC cell proliferation through lncRNA TRERNA1, which recruits EZH2 to the HOXA6 promoter, increasing H3K27me3 modification and suppressing HOXA6 expression; HOXA6 downregulation is required for KIAA1429-driven proliferation.","method":"RIP assay for m6A on TRERNA1, ChIP for EZH2 and H3K27me3 at HOXA6 promoter, siRNA/overexpression epistasis experiments, in vivo xenograft","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP confirming epigenetic mechanism at HOXA6 promoter with epistasis validation, single lab","pmids":["40640307"],"is_preprint":false}],"current_model":"HOXA6 is a homeodomain transcription factor that specifies axial identity in the vertebral column (cervicothoracic boundary), is epigenetically activated by the lncRNA Mistral via MLL1 recruitment, directly binds promoters of target genes such as ZBTB12, physically interacts with PBX2 as a co-factor, and promotes or suppresses proliferation, apoptosis, and metastasis in a context-dependent manner in cancer cells through regulation of the PI3K/Akt/ERK and Bcl-2/EMT pathways."},"narrative":{"teleology":[{"year":1994,"claim":"The first loss-of-function study established that HOXA6 is required for axial skeletal patterning at the cervicothoracic boundary, answering whether individual paralog group 6 HOX genes have non-redundant roles in vertebral specification.","evidence":"Gene-targeted knockout in mice with detailed skeletal analysis showing C7-to-T1 homeotic transformation","pmids":["7918106"],"confidence":"High","gaps":["Downstream transcriptional targets mediating the skeletal transformation were not identified","Redundancy with other paralog group 6 members was not resolved"]},{"year":2009,"claim":"Gain-of-function experiments demonstrated that HOXA6 is sufficient to drive hematopoietic progenitor proliferation and self-renewal, extending its functional scope beyond skeletal patterning.","evidence":"Retroviral overexpression in FDCP-Mix and Ba/F3 hematopoietic progenitor cells with colony formation and growth-factor withdrawal assays","pmids":["19157684"],"confidence":"Medium","gaps":["Direct transcriptional targets in hematopoietic cells were not identified","Loss-of-function confirmation in hematopoietic cells was not performed"]},{"year":2011,"claim":"Discovery of the lncRNA Mistral revealed an epigenetic activation mechanism for HOXA6 transcription, showing that a cis-encoded lncRNA recruits MLL1 to remodel chromatin at the Hoxa6 locus.","evidence":"RNA immunoprecipitation, chromatin conformation capture, MLL1 ChIP, and lncRNA knockdown/overexpression in mouse embryonic stem cells","pmids":["21925392"],"confidence":"High","gaps":["Whether Mistral is required for HOXA6 activation in all developmental contexts was not tested","Structural basis of Mistral–MLL1 interaction was not resolved"]},{"year":2018,"claim":"Bidirectional manipulation in colorectal cancer cells showed that HOXA6 promotes proliferation, migration, and EMT while suppressing apoptosis via Bcl-2 pathway modulation, establishing its oncogenic activity in this tissue.","evidence":"Overexpression and siRNA knockdown with CCK-8, colony formation, TUNEL, Transwell, and Western blotting in Caco2 and HT-29 cells","pmids":["29620285"],"confidence":"Medium","gaps":["Direct transcriptional targets driving EMT were not identified","In vivo tumor formation data were not provided"]},{"year":2019,"claim":"In contrast to colorectal cancer, HOXA6 overexpression in clear cell renal carcinoma suppressed proliferation and induced apoptosis via PI3K/Akt/ERK pathway inhibition, revealing tissue-dependent opposing roles.","evidence":"Overexpression and shRNA knockdown with Western blotting for p-Akt, p-ERK, Bcl-2, PTEN, Bax, and cleaved caspase-3 in 786-O and 769-P cells","pmids":["31081053"],"confidence":"Medium","gaps":["Direct promoter occupancy by HOXA6 on PI3K/Akt pathway components was not tested","Mechanism determining tissue-specific tumor-suppressive versus oncogenic activity is unknown"]},{"year":2020,"claim":"Identification of SOX10 as an upstream transcriptional activator of HOXA6 in spinal dorsal horn neurons placed HOXA6 within a TET1–SOX10 epigenetic cascade contributing to neuropathic pain.","evidence":"ChIP confirming SOX10 binding to HOXA6 promoter, bisulfite sequencing, siRNA knockdown, AAV overexpression, and behavioral pain assays in oxaliplatin-treated rats","pmids":["32428246"],"confidence":"Medium","gaps":["Direct HOXA6 transcriptional targets in nociceptive neurons were not defined","Whether HOXA6 is necessary for allodynia was not tested by direct Hoxa6 knockout"]},{"year":2021,"claim":"Co-immunoprecipitation revealed that HOXA6 physically interacts with and stabilizes PBX2, identifying a cofactor partnership that promotes metastasis in gastric cancer.","evidence":"Co-IP, siRNA knockdown, and orthotopic implantation metastasis model in gastric cancer cells","pmids":["33535170"],"confidence":"Medium","gaps":["Reciprocal Co-IP and endogenous interaction confirmation were not independently replicated","DNA-binding specificity changes conferred by the HOXA6–PBX2 complex were not mapped"]},{"year":2023,"claim":"ChIP and luciferase assays demonstrated that HOXA6 directly binds and transcriptionally activates the ZBTB12 promoter in cancer-associated fibroblasts, identifying a bona fide direct target gene.","evidence":"ChIP assay, luciferase reporter, and siRNA knockdown in gastric CAFs and 293T cells","pmids":["37708965"],"confidence":"Medium","gaps":["Genome-wide binding profile (ChIP-seq) for HOXA6 has not been reported","ZBTB12 downstream effectors mediating the pro-tumorigenic phenotype are unknown"]},{"year":2025,"claim":"An EZH2-mediated silencing mechanism was delineated whereby lncRNA TRERNA1 recruits EZH2 to the HOXA6 promoter to deposit H3K27me3, providing a second epigenetic regulatory axis (repressive) complementing the activating Mistral/MLL1 axis.","evidence":"ChIP for EZH2 and H3K27me3 at HOXA6 promoter, RIP for m6A-modified TRERNA1, epistasis experiments, and xenograft in NSCLC cells","pmids":["40640307"],"confidence":"Medium","gaps":["Interplay between Mistral-mediated activation and TRERNA1/EZH2-mediated repression at the same locus has not been studied","Whether this epigenetic switch operates in normal tissues is unknown"]},{"year":null,"claim":"A genome-wide map of HOXA6 direct transcriptional targets and the structural basis for its cofactor selectivity (e.g., PBX2 versus other TALE partners) remain undefined, preventing a unified model of its tissue-specific oncogenic versus tumor-suppressive activities.","evidence":"","pmids":[],"confidence":"Low","gaps":["No ChIP-seq or CUT&RUN data for HOXA6 in any system","Mechanism underlying context-dependent tumor-suppressive versus oncogenic behavior is unresolved","Role in adult homeostasis outside cancer settings is largely unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,7]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,7,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,7]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,7,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,10]}],"complexes":[],"partners":["PBX2","ZBTB12","MLL1","EZH2","SOX10"],"other_free_text":[]},"mechanistic_narrative":"HOXA6 is a homeodomain transcription factor that specifies axial positional identity and regulates cell proliferation, survival, and migration in developmental and oncogenic contexts. Targeted disruption in mice causes homeotic posterior transformation of the seventh cervical to the first thoracic vertebra, establishing its requirement for cervicothoracic boundary specification [PMID:7918106]. HOXA6 transcription is epigenetically controlled by MLL1 recruitment via the lncRNA Mistral and by EZH2-mediated H3K27me3 deposition directed through lncRNA TRERNA1, and its expression in the spinal cord is activated by SOX10 binding to the HOXA6 promoter [PMID:21925392, PMID:40640307, PMID:32428246]. HOXA6 directly binds target gene promoters such as ZBTB12, physically interacts with the cofactor PBX2, and modulates PI3K/Akt/ERK signaling, Bcl-2-dependent apoptosis, and epithelial–mesenchymal transition in a tissue-dependent manner [PMID:37708965, PMID:33535170, PMID:31081053, PMID:29620285]."},"prefetch_data":{"uniprot":{"accession":"P31267","full_name":"Homeobox protein Hox-A6","aliases":["Homeobox protein Hox-1B"],"length_aa":233,"mass_kda":26.3,"function":"Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P31267/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HOXA6","classification":"Not Classified","n_dependent_lines":12,"n_total_lines":1208,"dependency_fraction":0.009933774834437087},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/HOXA6","total_profiled":1310},"omim":[{"mim_id":"609907","title":"SEMAPHORIN 3D; SEMA3D","url":"https://www.omim.org/entry/609907"},{"mim_id":"142958","title":"HOMEOBOX A11; HOXA11","url":"https://www.omim.org/entry/142958"},{"mim_id":"142953","title":"HOMEOBOX A4; HOXA4","url":"https://www.omim.org/entry/142953"},{"mim_id":"142951","title":"HOMEOBOX A6; HOXA6","url":"https://www.omim.org/entry/142951"},{"mim_id":"142950","title":"HOMEOBOX A7; HOXA7","url":"https://www.omim.org/entry/142950"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear speckles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"fallopian tube","ntpm":11.2}],"url":"https://www.proteinatlas.org/search/HOXA6"},"hgnc":{"alias_symbol":[],"prev_symbol":["HOX1B","HOX1"]},"alphafold":{"accession":"P31267","domains":[{"cath_id":"1.10.10.60","chopping":"163-217","consensus_level":"medium","plddt":96.4024,"start":163,"end":217}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P31267","model_url":"https://alphafold.ebi.ac.uk/files/AF-P31267-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P31267-F1-predicted_aligned_error_v6.png","plddt_mean":62.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HOXA6","jax_strain_url":"https://www.jax.org/strain/search?query=HOXA6"},"sequence":{"accession":"P31267","fasta_url":"https://rest.uniprot.org/uniprotkb/P31267.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P31267/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P31267"}},"corpus_meta":[{"pmid":"1673020","id":"PMC_1673020","title":"Regionally restricted 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posterior transformation of the seventh cervical vertebra to the first thoracic vertebra, demonstrating Hoxa-6 is required for axial skeletal identity specification at positions approximating the anterior border of its expression domain in the prevertebrae.\",\n      \"method\": \"Gene targeting/knockout in mice with skeletal phenotype analysis\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined skeletal phenotype, replicated with Hoxa-4 in same study\",\n      \"pmids\": [\"7918106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The lncRNA Mistral (Mira), encoded in the spacer DNA between Hoxa6 and Hoxa7, activates Hoxa6 and Hoxa7 transcription by recruiting the epigenetic activator MLL1 to chromatin, inducing dynamic changes in chromosome conformation.\",\n      \"method\": \"RNA immunoprecipitation, chromatin conformation capture, lncRNA knockdown and overexpression, MLL1 ChIP in mouse embryonic stem cells\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (RIP, 3C, ChIP, KD/OE) in single study with rigorous controls\",\n      \"pmids\": [\"21925392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Enforced overexpression of HOXA6 in hematopoietic FDCP-Mix progenitor cells increases proliferation, colony formation, and potentiates factor-independent proliferation in Ba/F3 cells, demonstrating a direct role for HOXA6 in hematopoietic progenitor cell self-renewal and proliferation.\",\n      \"method\": \"Retroviral overexpression, colony formation assay, growth factor withdrawal assay in primary and cell line hematopoietic progenitors\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean gain-of-function with defined proliferative phenotype, single lab\",\n      \"pmids\": [\"19157684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HOXA6 physically interacts with and stabilizes the PBX2 protein in gastric cancer cells; HOXA6 and PBX2 cooperate to promote cell migration, invasion, and metastasis in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, STRING database interaction prediction, siRNA knockdown, orthotopic implantation in vivo\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP demonstrating physical interaction, supported by in vitro and in vivo functional assays, single lab\",\n      \"pmids\": [\"33535170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HOXA6 overexpression in clear cell renal cell carcinoma cells inhibits proliferation and induces apoptosis by suppressing the PI3K/Akt/ERK signaling pathway, reducing p-Akt, p-ERK and Bcl-2 levels while increasing PTEN, Bax and cleaved caspase-3.\",\n      \"method\": \"Plasmid overexpression and shRNA knockdown, Western blotting, flow cytometry, CCK-8 assay in 786-O and 769-P ccRCC cell lines\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss- and gain-of-function with pathway-level western blot readouts, single lab\",\n      \"pmids\": [\"31081053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HOXA6 promotes colorectal cancer cell proliferation, migration, and invasion while inhibiting apoptosis; it regulates apoptosis through the Bcl-2 pathway and promotes migration/invasion through induction of epithelial-mesenchymal transition (suppressing E-cadherin, upregulating N-cadherin and Vimentin).\",\n      \"method\": \"Plasmid overexpression and siRNA knockdown, CCK-8, colony formation, TUNEL, Transwell, wound-healing assays, Western blotting in Caco2 and HT-29 cells\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional manipulation with multiple phenotypic and molecular readouts, single lab\",\n      \"pmids\": [\"29620285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HOXA6 is upregulated in the spinal dorsal horn following oxaliplatin treatment downstream of SOX10: TET1-mediated demethylation of the SOX10 promoter leads to SOX10 upregulation, which then binds the HOXA6 promoter to drive HOXA6 transcription, contributing to mechanical allodynia.\",\n      \"method\": \"siRNA knockdown, reduced representation bisulfite sequencing, chromatin immunoprecipitation, AAV overexpression, behavioral pain assays in rat model\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirming SOX10 binding to HOXA6 promoter, bisulfite sequencing, multiple genetic interventions, single lab\",\n      \"pmids\": [\"32428246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HOXA6 transcriptionally activates ZBTB12 by binding to its promoter in gastric cancer-associated fibroblasts (CAFs), and this HOXA6-ZBTB12 axis promotes gastric cancer cell growth, migration, and invasiveness.\",\n      \"method\": \"ChIP assay confirming HOXA6 binding to ZBTB12 promoter, siRNA knockdown, luciferase reporter assay in 293T cells and CAFs\",\n      \"journal\": \"Acta pharmaceutica (Zagreb, Croatia)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirming direct promoter binding, supported by functional KD experiments, single lab\",\n      \"pmids\": [\"37708965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DDR1 promotes bladder cancer progression by targeting HOXA6 to inhibit ferroptosis; DDR1 knockdown-induced ferroptosis was rescued by HOXA6 knockdown, placing HOXA6 downstream of DDR1 in a pathway that maintains GSH, GPX4, and SLC7A11 levels and suppresses lipid peroxidation.\",\n      \"method\": \"siRNA knockdown, in vitro and in vivo functional assays, Western blotting for ferroptosis markers in bladder cancer cells\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — epistasis by double knockdown with defined ferroptosis markers, single lab, single study\",\n      \"pmids\": [\"40105492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Hoxa6 is differentially expressed in enteric neuronal lineages during enteric nervous system development; in Sox10Dom/+ Hirschsprung mouse mutants, Hoxa6 expression is altered in early developing neurons, implicating Hoxa6 in enteric neuron lineage allocation downstream of Sox10.\",\n      \"method\": \"Single-cell RNA sequencing, hybridization chain reaction (HCR) validation, gene regulatory network analysis in Sox10Dom/+ mouse ENS\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — associative scRNA-seq with HCR validation but no direct loss-of-function for Hoxa6; preprint\",\n      \"pmids\": [\"39345473\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KIAA1429 (VIRMA) promotes NSCLC cell proliferation through lncRNA TRERNA1, which recruits EZH2 to the HOXA6 promoter, increasing H3K27me3 modification and suppressing HOXA6 expression; HOXA6 downregulation is required for KIAA1429-driven proliferation.\",\n      \"method\": \"RIP assay for m6A on TRERNA1, ChIP for EZH2 and H3K27me3 at HOXA6 promoter, siRNA/overexpression epistasis experiments, in vivo xenograft\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirming epigenetic mechanism at HOXA6 promoter with epistasis validation, single lab\",\n      \"pmids\": [\"40640307\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HOXA6 is a homeodomain transcription factor that specifies axial identity in the vertebral column (cervicothoracic boundary), is epigenetically activated by the lncRNA Mistral via MLL1 recruitment, directly binds promoters of target genes such as ZBTB12, physically interacts with PBX2 as a co-factor, and promotes or suppresses proliferation, apoptosis, and metastasis in a context-dependent manner in cancer cells through regulation of the PI3K/Akt/ERK and Bcl-2/EMT pathways.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"HOXA6 is a homeodomain transcription factor that specifies axial positional identity and regulates cell proliferation, survival, and migration in developmental and oncogenic contexts. Targeted disruption in mice causes homeotic posterior transformation of the seventh cervical to the first thoracic vertebra, establishing its requirement for cervicothoracic boundary specification [PMID:7918106]. HOXA6 transcription is epigenetically controlled by MLL1 recruitment via the lncRNA Mistral and by EZH2-mediated H3K27me3 deposition directed through lncRNA TRERNA1, and its expression in the spinal cord is activated by SOX10 binding to the HOXA6 promoter [PMID:21925392, PMID:40640307, PMID:32428246]. HOXA6 directly binds target gene promoters such as ZBTB12, physically interacts with the cofactor PBX2, and modulates PI3K/Akt/ERK signaling, Bcl-2-dependent apoptosis, and epithelial–mesenchymal transition in a tissue-dependent manner [PMID:37708965, PMID:33535170, PMID:31081053, PMID:29620285].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"The first loss-of-function study established that HOXA6 is required for axial skeletal patterning at the cervicothoracic boundary, answering whether individual paralog group 6 HOX genes have non-redundant roles in vertebral specification.\",\n      \"evidence\": \"Gene-targeted knockout in mice with detailed skeletal analysis showing C7-to-T1 homeotic transformation\",\n      \"pmids\": [\"7918106\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Downstream transcriptional targets mediating the skeletal transformation were not identified\",\n        \"Redundancy with other paralog group 6 members was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Gain-of-function experiments demonstrated that HOXA6 is sufficient to drive hematopoietic progenitor proliferation and self-renewal, extending its functional scope beyond skeletal patterning.\",\n      \"evidence\": \"Retroviral overexpression in FDCP-Mix and Ba/F3 hematopoietic progenitor cells with colony formation and growth-factor withdrawal assays\",\n      \"pmids\": [\"19157684\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct transcriptional targets in hematopoietic cells were not identified\",\n        \"Loss-of-function confirmation in hematopoietic cells was not performed\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery of the lncRNA Mistral revealed an epigenetic activation mechanism for HOXA6 transcription, showing that a cis-encoded lncRNA recruits MLL1 to remodel chromatin at the Hoxa6 locus.\",\n      \"evidence\": \"RNA immunoprecipitation, chromatin conformation capture, MLL1 ChIP, and lncRNA knockdown/overexpression in mouse embryonic stem cells\",\n      \"pmids\": [\"21925392\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether Mistral is required for HOXA6 activation in all developmental contexts was not tested\",\n        \"Structural basis of Mistral–MLL1 interaction was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Bidirectional manipulation in colorectal cancer cells showed that HOXA6 promotes proliferation, migration, and EMT while suppressing apoptosis via Bcl-2 pathway modulation, establishing its oncogenic activity in this tissue.\",\n      \"evidence\": \"Overexpression and siRNA knockdown with CCK-8, colony formation, TUNEL, Transwell, and Western blotting in Caco2 and HT-29 cells\",\n      \"pmids\": [\"29620285\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct transcriptional targets driving EMT were not identified\",\n        \"In vivo tumor formation data were not provided\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"In contrast to colorectal cancer, HOXA6 overexpression in clear cell renal carcinoma suppressed proliferation and induced apoptosis via PI3K/Akt/ERK pathway inhibition, revealing tissue-dependent opposing roles.\",\n      \"evidence\": \"Overexpression and shRNA knockdown with Western blotting for p-Akt, p-ERK, Bcl-2, PTEN, Bax, and cleaved caspase-3 in 786-O and 769-P cells\",\n      \"pmids\": [\"31081053\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct promoter occupancy by HOXA6 on PI3K/Akt pathway components was not tested\",\n        \"Mechanism determining tissue-specific tumor-suppressive versus oncogenic activity is unknown\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of SOX10 as an upstream transcriptional activator of HOXA6 in spinal dorsal horn neurons placed HOXA6 within a TET1–SOX10 epigenetic cascade contributing to neuropathic pain.\",\n      \"evidence\": \"ChIP confirming SOX10 binding to HOXA6 promoter, bisulfite sequencing, siRNA knockdown, AAV overexpression, and behavioral pain assays in oxaliplatin-treated rats\",\n      \"pmids\": [\"32428246\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct HOXA6 transcriptional targets in nociceptive neurons were not defined\",\n        \"Whether HOXA6 is necessary for allodynia was not tested by direct Hoxa6 knockout\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Co-immunoprecipitation revealed that HOXA6 physically interacts with and stabilizes PBX2, identifying a cofactor partnership that promotes metastasis in gastric cancer.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, and orthotopic implantation metastasis model in gastric cancer cells\",\n      \"pmids\": [\"33535170\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Reciprocal Co-IP and endogenous interaction confirmation were not independently replicated\",\n        \"DNA-binding specificity changes conferred by the HOXA6–PBX2 complex were not mapped\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"ChIP and luciferase assays demonstrated that HOXA6 directly binds and transcriptionally activates the ZBTB12 promoter in cancer-associated fibroblasts, identifying a bona fide direct target gene.\",\n      \"evidence\": \"ChIP assay, luciferase reporter, and siRNA knockdown in gastric CAFs and 293T cells\",\n      \"pmids\": [\"37708965\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Genome-wide binding profile (ChIP-seq) for HOXA6 has not been reported\",\n        \"ZBTB12 downstream effectors mediating the pro-tumorigenic phenotype are unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"An EZH2-mediated silencing mechanism was delineated whereby lncRNA TRERNA1 recruits EZH2 to the HOXA6 promoter to deposit H3K27me3, providing a second epigenetic regulatory axis (repressive) complementing the activating Mistral/MLL1 axis.\",\n      \"evidence\": \"ChIP for EZH2 and H3K27me3 at HOXA6 promoter, RIP for m6A-modified TRERNA1, epistasis experiments, and xenograft in NSCLC cells\",\n      \"pmids\": [\"40640307\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Interplay between Mistral-mediated activation and TRERNA1/EZH2-mediated repression at the same locus has not been studied\",\n        \"Whether this epigenetic switch operates in normal tissues is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A genome-wide map of HOXA6 direct transcriptional targets and the structural basis for its cofactor selectivity (e.g., PBX2 versus other TALE partners) remain undefined, preventing a unified model of its tissue-specific oncogenic versus tumor-suppressive activities.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No ChIP-seq or CUT&RUN data for HOXA6 in any system\",\n        \"Mechanism underlying context-dependent tumor-suppressive versus oncogenic behavior is unresolved\",\n        \"Role in adult homeostasis outside cancer settings is largely unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 7, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 7, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PBX2\",\n      \"ZBTB12\",\n      \"MLL1\",\n      \"EZH2\",\n      \"SOX10\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}