{"gene":"HOXB6","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1995,"finding":"Hoxb-5 and Hoxb-6 function together to specify cervicothoracic vertebral identity; targeted disruption of hoxb-6 causes missing first rib, bifid second rib, and anteriorizing homeotic transformations of vertebrae C6–T1. Trans-heterozygotes (hoxb-5-/hoxb-6+) show the same cervicothoracic phenotype, demonstrating nonallelic noncomplementation and cooperative genetic interaction between the two adjacent genes.","method":"Gene targeting in ES cells / knockout mice; genetic complementation test (trans-heterozygotes); skeletal analysis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined skeletal phenotype, replicated across both single and double mutants with rigorous genetic epistasis","pmids":["7828847"],"is_preprint":false},{"year":2004,"finding":"HOXB6 overexpression in murine bone marrow expands hematopoietic stem cells and myeloid precursors while inhibiting erythropoiesis and lymphopoiesis, immortalizes a myelomonocytic precursor in vitro, and causes acute myeloid leukemia in vivo. These effects are largely dependent on DNA binding but independent of direct interaction with PBX1 co-factor. Co-expression of MEIS1 dramatically accelerates AML onset.","method":"Retrovirus-mediated gene transfer into murine bone marrow; structure-function analysis with DNA-binding and PBX1-interaction mutants; in vivo transplantation; clonogenic assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — loss/gain of function with defined hematopoietic phenotypes, structure-function mutagenesis, and cooperative interaction with MEIS1 in single study","pmids":["15522959"],"is_preprint":false},{"year":2004,"finding":"HOXB6 represses alpha- and gamma-globin mRNA levels in a DNA-binding-dependent manner. HOXB6 protein co-precipitates endogenous CBP (CREB-binding protein) from nuclear and cytoplasmic compartments of transfected K562 cells and from murine fetal liver cells. The CBP interaction is localized to the homeodomain but does not require helix 3. PBX co-factor interaction is not required for HOXB6 biological activity in this model.","method":"Stable transfection of K562 cells; RT-PCR for globin transcripts; co-immunoprecipitation of endogenous CBP with exogenous and endogenous HOXB6; homeodomain deletion/mutation analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP of endogenous proteins plus structure-function mutagenesis with defined transcriptional readout","pmids":["15269212"],"is_preprint":false},{"year":2000,"finding":"HOXB6 protein undergoes a change in subcellular localization during epidermal development: it is cytoplasmic in fetal epidermis but substantially nuclear in adult skin. A truncated HOXB6 isoform lacking the homeodomain is expressed in undifferentiated keratinocytes and is largely cytoplasmic, while full-length HOXB6 localizes to the nucleus. Nuclear HOXB6 in adult skin does not co-localize with PBX proteins, suggesting PBX-independent nuclear function.","method":"Immunohistochemistry; Western blot; GFP-fusion protein localization in live cells; RNA analysis of isoforms","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2/3 — direct localization by IHC and GFP fusion with functional isoform correlation, single lab","pmids":["10906782"],"is_preprint":false},{"year":1999,"finding":"HOXB6 (Hoxb-6) is phosphorylated in vivo at serine-214 by casein kinase II (CK-II). This phosphorylation site is conserved across species. Hoxb-6 is also phosphorylated in vitro by cAMP-dependent protein kinase. The same CK-II phosphopeptide detected in vitro is phosphorylated in embryonic mouse spinal cord in vivo.","method":"Baculovirus expression in Sf9 cells; in vitro kinase assays with purified CK-II and PKA; two-dimensional tryptic phosphopeptide mapping; immunoprecipitation from mouse embryonic spinal cords","journal":"The Journal of experimental zoology","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay plus in vivo phosphopeptide mapping confirming same site","pmids":["10327653"],"is_preprint":false},{"year":2015,"finding":"The linker region (LR) connecting the Hoxb6 homeodomain and the hexapeptide is essential for rib-promoting activity in mice. LR-defective Hoxb6 can still bind a target enhancer together with Pax3 but acts as a dominant negative, indicating the LR recruits additional regulatory factors to target DNA. Hoxb6 also regulates somitogenesis by dysregulating Lfng expression in a manner independent of its rib-promoting activity.","method":"Transgenic mice expressing LR-deletion mutant HOXB6; ChIP/enhancer binding assays showing Hoxb6-Pax3 co-occupancy; analysis of Lfng expression; skeletal phenotype analysis","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 — in vivo mutagenesis with defined skeletal and segmentation phenotypes, dominant-negative mechanism established, multiple orthogonal readouts","pmids":["26718008"],"is_preprint":false},{"year":2000,"finding":"Targeted disruption of Hoxb-6 in mice results in an increased number of early erythroid progenitor cells (BFU-E) in bone marrow and fetal liver, while differentiation of other hematopoietic lineages is unaffected. This establishes a role for Hoxb-6 in controlling the generation, proliferation, or survival of erythroid progenitors.","method":"Gene targeting in mice; clonogenic progenitor cell assays (colony-forming unit assays for multiple lineages)","journal":"American journal of hematology","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with specific hematopoietic cellular phenotype, single lab","pmids":["10996827"],"is_preprint":false},{"year":2002,"finding":"Enforced expression of HOXB6 in promyelocytic NB4 cells or myeloblastic HL60 cells inhibits granulocytic or monocytic maturation respectively. HOXB6 expression is transiently induced during normal granulocytopoiesis and monocytopoiesis with an initial induction followed by blockade at early maturation, indicating that regulated HOXB6 expression is required for normal myeloid differentiation.","method":"Retroviral overexpression in NB4 and HL60 cell lines; differentiation assays with morphological and molecular readouts","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2/3 — gain-of-function with defined differentiation phenotype in two cell line models, single lab","pmids":["12094253"],"is_preprint":false},{"year":1993,"finding":"Three distinct cis-regulatory elements govern Hoxb-6 expression: a limb/lateral plate mesoderm (LPM) enhancer directing expression to limb buds and ventro-lateral mesenchyme, an element for ventral spinal cord expression, and an element for mesonephric structures. The limb/LPM element functions as an orientation- and promoter-independent enhancer.","method":"Transgenic mouse embryos carrying LacZ reporter gene fused to different Hoxb-6 genomic fragments; 13.2 kb genomic region systematically analyzed","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 — systematic transgenic reporter dissection, single lab, multiple constructs","pmids":["8104549"],"is_preprint":false},{"year":2020,"finding":"HOXB6 is a direct transcriptional repressor of Sox9: HOXB6 protein binds to the Sox9 promoter and inhibits Sox9 expression. In liver injury, miR-126 suppresses HOXB6 translation, relieving Sox9 repression and enabling SOX9+ liver progenitor cell proliferation and differentiation.","method":"Luciferase reporter assay with Sox9 promoter; chromatin immunoprecipitation (ChIP) showing HOXB6 binding to Sox9 promoter; miR-126 target validation; CCl4 liver injury model","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP demonstrating direct promoter binding plus functional miRNA-mediated regulation with in vivo model, single lab","pmids":["32763157"],"is_preprint":false},{"year":2016,"finding":"Hoxb6 controls multiple independent aspects of skeletal patterning at the cervico-thoracic junction, and its function is subject to modulation by genetic background, establishing Hox-controlled skeletal pattern as a quantitative trait with gene-gene interactions.","method":"Hoxb6 knockout mice on multiple genetic backgrounds; quantitative skeletal phenotyping","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with quantitative phenotypic analysis across genetic backgrounds, single lab","pmids":["26800342"],"is_preprint":false},{"year":2024,"finding":"Loss of HOXB6 in pancreatic cancer cells inhibits cell proliferation, induces apoptosis and senescence, enhances gemcitabine sensitivity, and affects transcription of immune response pathways, resulting in increased sensitivity to macrophage anti-tumorigenic activity.","method":"siRNA/shRNA knockdown in PDAC cell lines; proliferation, apoptosis, and senescence assays; transcriptomic analysis; co-culture with macrophages; drug sensitivity assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — KD with cellular phenotypes but no direct molecular mechanism established, preprint not peer-reviewed","pmids":["bio_10.1101_2024.09.06.611619"],"is_preprint":true}],"current_model":"HOXB6 is a homeodomain transcription factor that binds DNA (requiring an intact homeodomain and linker region), is phosphorylated at Ser-214 by casein kinase II in vivo, physically interacts with CBP/p300 histone acetyltransferase via its homeodomain to repress target genes (including globins), cooperates genetically with adjacent HOXB5 and with MEIS1 in a PBX1-independent manner to control hematopoietic stem cell expansion and myeloid differentiation, specifies cervicothoracic vertebral identity and rib formation through LR-domain-dependent recruitment of regulatory cofactors (including Pax3) to target enhancers, controls erythroid progenitor numbers in the bone marrow, directly represses Sox9 transcription in the liver, and undergoes differentiation-dependent isoform switching and nuclear/cytoplasmic relocalization in epithelial tissues."},"narrative":{"teleology":[{"year":1993,"claim":"Mapping of cis-regulatory elements controlling Hoxb6 expression revealed that distinct enhancers independently drive expression in limb/lateral plate mesoderm, ventral spinal cord, and mesonephros, establishing the modular transcriptional control underlying HOXB6's tissue-specific roles.","evidence":"Transgenic LacZ reporter dissection of 13.2 kb Hoxb6 genomic region in mouse embryos","pmids":["8104549"],"confidence":"Medium","gaps":["Trans-acting factors binding these enhancers were not identified","No connection to downstream target genes"]},{"year":1995,"claim":"Gene disruption established that HOXB6 specifies cervicothoracic vertebral identity and cooperates genetically with adjacent HOXB5, resolving the functional contribution of a single posterior HOX gene to axial patterning and demonstrating nonallelic noncomplementation between paralogous HOX genes.","evidence":"Targeted knockout mice; trans-heterozygote genetic complementation; skeletal analysis","pmids":["7828847"],"confidence":"High","gaps":["Downstream target genes mediating vertebral identity unknown","Mechanism of HOXB5–HOXB6 cooperation at the molecular level not defined"]},{"year":1999,"claim":"Identification of CK-II-mediated phosphorylation at Ser-214 in vivo provided the first post-translational regulatory mechanism for HOXB6, raising the question of how phosphorylation modulates DNA binding or cofactor interactions.","evidence":"In vitro kinase assays with purified CK-II; 2D tryptic phosphopeptide mapping from mouse embryonic spinal cord immunoprecipitates","pmids":["10327653"],"confidence":"High","gaps":["Functional consequence of Ser-214 phosphorylation on transcriptional activity not tested","No phospho-dead mutant phenotype in vivo"]},{"year":2000,"claim":"Two studies clarified HOXB6's roles beyond skeletal patterning: knockout mice showed expanded erythroid progenitors in bone marrow, and differentiation-dependent isoform switching with nuclear/cytoplasmic relocalization was documented in skin, establishing HOXB6 as a regulator of both hematopoietic and epithelial differentiation.","evidence":"Hoxb6 knockout clonogenic progenitor assays; immunohistochemistry and GFP-fusion localization in keratinocytes","pmids":["10996827","10906782"],"confidence":"Medium","gaps":["Target genes mediating erythroid progenitor control not identified","Mechanism controlling isoform switching unclear","Whether truncated cytoplasmic isoform has independent function not tested"]},{"year":2002,"claim":"Enforced expression experiments showed HOXB6 blocks granulocytic and monocytic maturation and is transiently induced during normal myelopoiesis, indicating that dynamic HOXB6 expression levels gate myeloid differentiation progression.","evidence":"Retroviral overexpression in NB4 and HL60 cells; morphological and molecular differentiation readouts","pmids":["12094253"],"confidence":"Medium","gaps":["Direct transcriptional targets in myeloid cells not identified","Loss-of-function in myeloid lineage not performed"]},{"year":2004,"claim":"Structure-function studies resolved that HOXB6's oncogenic and transcriptional activities require DNA binding but not PBX1 interaction, and that HOXB6 physically engages CBP/p300 through its homeodomain to repress globin genes, while cooperation with MEIS1 accelerates leukemogenesis.","evidence":"Retroviral BM transduction with domain mutants and in vivo transplantation; co-IP of endogenous CBP with HOXB6 in K562 and fetal liver cells; globin RT-PCR","pmids":["15522959","15269212"],"confidence":"High","gaps":["Genome-wide direct targets in hematopoietic cells not mapped","How CBP interaction leads to repression rather than activation not mechanistically resolved","Whether MEIS1 and HOXB6 form a physical complex not tested"]},{"year":2015,"claim":"The linker region between the homeodomain and hexapeptide was shown to be essential for rib-promoting activity by recruiting additional regulatory cofactors to target enhancers (co-occupied with Pax3), separating HOXB6's rib-patterning function from its role in somitogenesis via Lfng regulation.","evidence":"Transgenic mice expressing LR-deletion mutant; ChIP showing Hoxb6-Pax3 co-occupancy; Lfng and skeletal phenotype analysis","pmids":["26718008"],"confidence":"High","gaps":["Identity of LR-recruited cofactors unknown","Whether Pax3 interaction is direct or enhancer-mediated not resolved"]},{"year":2016,"claim":"Quantitative phenotyping across genetic backgrounds showed HOXB6 skeletal functions are modulated by genetic modifiers, establishing Hox-controlled skeletal pattern as a quantitative trait.","evidence":"Hoxb6 knockout mice on multiple inbred backgrounds; quantitative skeletal scoring","pmids":["26800342"],"confidence":"Medium","gaps":["Modifier loci not mapped","Molecular basis of background sensitivity unknown"]},{"year":2020,"claim":"HOXB6 was identified as a direct transcriptional repressor of Sox9 in the liver, with miR-126-mediated translational suppression of HOXB6 enabling SOX9+ progenitor activation during liver injury, linking HOXB6 to adult tissue regeneration.","evidence":"ChIP showing HOXB6 binding at Sox9 promoter; luciferase reporters; miR-126 target validation; CCl4 liver injury model","pmids":["32763157"],"confidence":"Medium","gaps":["Whether HOXB6 represses Sox9 in other tissues not tested","Additional HOXB6 target genes in liver not identified"]},{"year":null,"claim":"Key unresolved questions include the genome-wide direct target repertoire of HOXB6 in hematopoietic and skeletal contexts, the identity of linker-region-recruited cofactors essential for rib formation, the functional consequence of CK-II phosphorylation, and how HOXB6–CBP interaction mediates transcriptional repression rather than activation.","evidence":"","pmids":[],"confidence":"High","gaps":["No genome-wide ChIP-seq or CUT&RUN target map in any tissue","No structural model of HOXB6–CBP or HOXB6–cofactor complexes","Functional role of Ser-214 phosphorylation untested by mutagenesis in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1,2,5,9]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,7,9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,3,9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,5,10]}],"complexes":[],"partners":["CBP","HOXB5","MEIS1","PAX3"],"other_free_text":[]},"mechanistic_narrative":"HOXB6 is a homeodomain transcription factor that specifies cervicothoracic vertebral identity, controls rib formation, and regulates hematopoietic lineage decisions. Targeted disruption in mice causes anteriorizing vertebral transformations and rib defects through a mechanism requiring its linker region for cofactor recruitment (including Pax3) to target enhancers, while genetic cooperation with HOXB5 establishes cervicothoracic identity [PMID:7828847, PMID:26718008]. HOXB6 physically interacts with CBP/p300 via its homeodomain to repress globin gene transcription, directly represses Sox9 by binding its promoter, and restrains erythroid progenitor expansion in bone marrow, while its overexpression expands hematopoietic stem cells and cooperates with MEIS1 to induce acute myeloid leukemia in a DNA-binding-dependent but PBX1-independent manner [PMID:15269212, PMID:15522959, PMID:10996827, PMID:32763157]. HOXB6 is phosphorylated at Ser-214 by casein kinase II in vivo and undergoes differentiation-dependent isoform switching and nuclear/cytoplasmic relocalization in epithelial tissues [PMID:10327653, PMID:10906782]."},"prefetch_data":{"uniprot":{"accession":"P17509","full_name":"Homeobox protein Hox-B6","aliases":["Homeobox protein Hox-2.2","Homeobox protein Hox-2B","Homeobox protein Hu-2"],"length_aa":224,"mass_kda":25.4,"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/P17509/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HOXB6","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ANKRD17","stoichiometry":4.0},{"gene":"CANX","stoichiometry":0.2},{"gene":"DDOST","stoichiometry":0.2},{"gene":"OST4","stoichiometry":0.2},{"gene":"PSME3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/HOXB6","total_profiled":1310},"omim":[{"mim_id":"615162","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 35; MRT35","url":"https://www.omim.org/entry/615162"},{"mim_id":"607759","title":"INTEGRIN, ALPHA-2B; ITGA2B","url":"https://www.omim.org/entry/607759"},{"mim_id":"249000","title":"MECKEL SYNDROME, TYPE 1; MKS1","url":"https://www.omim.org/entry/249000"},{"mim_id":"173470","title":"INTEGRIN, BETA-3; ITGB3","url":"https://www.omim.org/entry/173470"},{"mim_id":"142962","title":"HOMEOBOX B7; HOXB7","url":"https://www.omim.org/entry/142962"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"epididymis","ntpm":38.0},{"tissue":"kidney","ntpm":57.8}],"url":"https://www.proteinatlas.org/search/HOXB6"},"hgnc":{"alias_symbol":[],"prev_symbol":["HOX2","HOX2B"]},"alphafold":{"accession":"P17509","domains":[{"cath_id":"1.10.10.60","chopping":"153-214","consensus_level":"medium","plddt":93.5619,"start":153,"end":214}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P17509","model_url":"https://alphafold.ebi.ac.uk/files/AF-P17509-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P17509-F1-predicted_aligned_error_v6.png","plddt_mean":64.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HOXB6","jax_strain_url":"https://www.jax.org/strain/search?query=HOXB6"},"sequence":{"accession":"P17509","fasta_url":"https://rest.uniprot.org/uniprotkb/P17509.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P17509/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P17509"}},"corpus_meta":[{"pmid":"2571936","id":"PMC_2571936","title":"Segmental 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regions and in situ localization of transcripts.","date":"1990","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/1968004","citation_count":47,"is_preprint":false},{"pmid":"17003840","id":"PMC_17003840","title":"Mutation screening of BMP4, BMP7, HOXA4 and HOXB6 genes in Chinese patients with hypospadias.","date":"2006","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/17003840","citation_count":46,"is_preprint":false},{"pmid":"10330333","id":"PMC_10330333","title":"Evolution of a HOXB6 intergenic region within the great apes and humans.","date":"1999","source":"Journal of human evolution","url":"https://pubmed.ncbi.nlm.nih.gov/10330333","citation_count":46,"is_preprint":false},{"pmid":"1972280","id":"PMC_1972280","title":"A yeast artificial chromosome containing the mouse homeobox cluster Hox-2.","date":"1990","source":"Proceedings of the National Academy of Sciences of the United States of 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Research","url":"https://pubmed.ncbi.nlm.nih.gov/1359901","citation_count":41,"is_preprint":false},{"pmid":"10906782","id":"PMC_10906782","title":"Changes in HOXB6 homeodomain protein structure and localization during human epidermal development and differentiation.","date":"2000","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/10906782","citation_count":38,"is_preprint":false},{"pmid":"9292516","id":"PMC_9292516","title":"Lineage-specific regulation of hematopoiesis by HOX-B8 (HOX-2.4): inhibition of granulocytic differentiation and potentiation of monocytic differentiation.","date":"1997","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/9292516","citation_count":38,"is_preprint":false},{"pmid":"32420798","id":"PMC_32420798","title":"ST8SIA6-AS1 promotes hepatocellular carcinoma by absorbing miR-5195-3p to regulate HOXB6.","date":"2020","source":"Cancer biology & 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Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/8104549","citation_count":33,"is_preprint":false},{"pmid":"2875852","id":"PMC_2875852","title":"The murine Hox-2 cluster of homeo box containing genes maps distal on chromosome 11 near the tail-short (Ts) locus.","date":"1986","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/2875852","citation_count":32,"is_preprint":false},{"pmid":"1352841","id":"PMC_1352841","title":"DNA sequence polymorphism within hominoid species exceeds the number of phylogenetically informative characters for a HOX2 locus.","date":"1992","source":"Molecular biology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/1352841","citation_count":30,"is_preprint":false},{"pmid":"12094253","id":"PMC_12094253","title":"Expression pattern of HOXB6 homeobox gene in myelomonocytic differentiation and acute myeloid leukemia.","date":"2002","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/12094253","citation_count":28,"is_preprint":false},{"pmid":"15269212","id":"PMC_15269212","title":"HOXB6 protein is bound to CREB-binding protein and represses globin expression in a DNA binding-dependent, PBX interaction-independent process.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15269212","citation_count":28,"is_preprint":false},{"pmid":"2892751","id":"PMC_2892751","title":"The mouse Hox2.3 homeobox-containing gene: regulation in differentiating pluripotent stem cells and expression pattern in embryos.","date":"1987","source":"Differentiation; research in biological diversity","url":"https://pubmed.ncbi.nlm.nih.gov/2892751","citation_count":25,"is_preprint":false},{"pmid":"2895022","id":"PMC_2895022","title":"A zebrafish homologue of the murine Hox-2.1 gene.","date":"1988","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/2895022","citation_count":25,"is_preprint":false},{"pmid":"2904810","id":"PMC_2904810","title":"In situ hybridization patterns of zebrafish homeobox genes homologous to Hox-2.1 and En-2 of mouse.","date":"1988","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/2904810","citation_count":24,"is_preprint":false},{"pmid":"26718008","id":"PMC_26718008","title":"Hoxb6 can interfere with somitogenesis in the posterior embryo through a mechanism independent of its rib-promoting activity.","date":"2015","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/26718008","citation_count":23,"is_preprint":false},{"pmid":"1677811","id":"PMC_1677811","title":"Characterization of the murine Hox-2.3 promoter: involvement of the transcription factor USF (MLTF).","date":"1991","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/1677811","citation_count":22,"is_preprint":false},{"pmid":"2896141","id":"PMC_2896141","title":"The Hox-2 homeo box gene complex on mouse chromosome 11 is closely linked to Re.","date":"1988","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/2896141","citation_count":18,"is_preprint":false},{"pmid":"18553509","id":"PMC_18553509","title":"Unique spatial and cellular expression patterns of Hoxa5, Hoxb4, and Hoxb6 proteins in normal developing murine lung are modified in pulmonary hypoplasia.","date":"2008","source":"Birth defects research. Part A, Clinical and molecular teratology","url":"https://pubmed.ncbi.nlm.nih.gov/18553509","citation_count":17,"is_preprint":false},{"pmid":"1673811","id":"PMC_1673811","title":"A deletion and a rearrangement distinguish between the intracisternal A-particle of Hox-2.4 and that of interleukin-3 in the same leukemic cells.","date":"1991","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/1673811","citation_count":17,"is_preprint":false},{"pmid":"1683482","id":"PMC_1683482","title":"Possible role of DNA topoisomerase II on transcription of the homeobox gene Hox-2.1 in F9 embryonal carcinoma cells.","date":"1991","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/1683482","citation_count":17,"is_preprint":false},{"pmid":"32763157","id":"PMC_32763157","title":"MiR-126 Regulates Properties of SOX9+ Liver Progenitor Cells during Liver Repair by Targeting Hoxb6.","date":"2020","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32763157","citation_count":13,"is_preprint":false},{"pmid":"8097725","id":"PMC_8097725","title":"Induction of HOX-2 genes in P19 embryocarcinoma cells is dependent on retinoic acid receptor alpha.","date":"1993","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/8097725","citation_count":13,"is_preprint":false},{"pmid":"10327653","id":"PMC_10327653","title":"Phylogenetically conserved CK-II phosphorylation site of the murine homeodomain protein Hoxb-6.","date":"1999","source":"The Journal of experimental zoology","url":"https://pubmed.ncbi.nlm.nih.gov/10327653","citation_count":12,"is_preprint":false},{"pmid":"1349742","id":"PMC_1349742","title":"The murine Hox-2.4 promoter contains a functional octamer motif.","date":"1992","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/1349742","citation_count":11,"is_preprint":false},{"pmid":"37356630","id":"PMC_37356630","title":"Hsa_circ_0007031 promotes the proliferation and migration of osteosarcoma cells by sponging miR-196a-5p to regulate the HOXB6.","date":"2023","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37356630","citation_count":10,"is_preprint":false},{"pmid":"16051213","id":"PMC_16051213","title":"Ets identified as a trans-regulatory factor of amphioxus Hox2 by transgenic analysis using ascidian embryos.","date":"2005","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/16051213","citation_count":10,"is_preprint":false},{"pmid":"2907403","id":"PMC_2907403","title":"Restriction fragment length polymorphism and chromosome mapping of a mouse homeo box gene, Hox-2.1.","date":"1988","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/2907403","citation_count":10,"is_preprint":false},{"pmid":"26800342","id":"PMC_26800342","title":"Developmental Patterning as a Quantitative Trait: Genetic Modulation of the Hoxb6 Mutant Skeletal Phenotype.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26800342","citation_count":8,"is_preprint":false},{"pmid":"8786996","id":"PMC_8786996","title":"The limb/LPM enhancer of the murine Hoxb6 gene: reporter gene analysis in transgenic embryos and studies of DNA-protein interactions.","date":"1996","source":"Pharmaceutica acta Helvetiae","url":"https://pubmed.ncbi.nlm.nih.gov/8786996","citation_count":7,"is_preprint":false},{"pmid":"7890121","id":"PMC_7890121","title":"The 5'-sequence of the murine Hox-b3 (Hox-2.7) gene and its intron contain multiple transcription-regulatory elements.","date":"1994","source":"The International journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7890121","citation_count":6,"is_preprint":false},{"pmid":"1359814","id":"PMC_1359814","title":"Assignment of the HOX2 and HOX3 gene clusters to the bovine chromosome regions 19q17-qter and 5q14-23.","date":"1992","source":"Animal genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1359814","citation_count":5,"is_preprint":false},{"pmid":"2882472","id":"PMC_2882472","title":"A TaqI restriction fragment length polymorphism at the Hox-2.1 locus cosegregates with the Dlb-1 locus on mouse chromosome 11.","date":"1987","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/2882472","citation_count":3,"is_preprint":false},{"pmid":"1937017","id":"PMC_1937017","title":"Production of mouse Hox-2.1 protein in Escherichia coli: characterisation of in vitro binding to DNA.","date":"1991","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/1937017","citation_count":2,"is_preprint":false},{"pmid":"1353046","id":"PMC_1353046","title":"DNA-binding activity of the murine homeodomain protein Hox-2.3 produced by a hybrid phage T7/vaccinia virus system.","date":"1992","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/1353046","citation_count":1,"is_preprint":false},{"pmid":"12536483","id":"PMC_12536483","title":"[Influence of human cytomegalovirus infection on the expression of HOXB5, HOXB6, HOXB7, and HOXB8 genes in gliomaous cells].","date":"2001","source":"Hunan yi ke da xue xue bao = Hunan yike daxue xuebao = Bulletin of Hunan Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/12536483","citation_count":0,"is_preprint":false},{"pmid":"12536675","id":"PMC_12536675","title":"[Influence of human cytomegalovirus infection on the expressions of HOXB1, HOXB5, HOXB6, and HOXB9 genes in human embryo lung cells].","date":"2001","source":"Hunan yi ke da xue xue bao = Hunan yike daxue xuebao = Bulletin of Hunan Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/12536675","citation_count":0,"is_preprint":false},{"pmid":"8619923","id":"PMC_8619923","title":"The Hox-2.4 gene is not involved in the generation of IL-3 dependent multipotent FDCP-mix cell lines.","date":"1995","source":"Growth factors (Chur, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/8619923","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.09.06.611619","title":"HOXB6 and HOXB8 control immune-cancer cell interactions in pancreatic cancer","date":"2024-09-06","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.06.611619","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":33100,"output_tokens":3211,"usd":0.073733},"stage2":{"model":"claude-opus-4-6","input_tokens":6558,"output_tokens":2518,"usd":0.14361},"total_usd":0.217343,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"Hoxb-5 and Hoxb-6 function together to specify cervicothoracic vertebral identity; targeted disruption of hoxb-6 causes missing first rib, bifid second rib, and anteriorizing homeotic transformations of vertebrae C6–T1. Trans-heterozygotes (hoxb-5-/hoxb-6+) show the same cervicothoracic phenotype, demonstrating nonallelic noncomplementation and cooperative genetic interaction between the two adjacent genes.\",\n      \"method\": \"Gene targeting in ES cells / knockout mice; genetic complementation test (trans-heterozygotes); skeletal analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined skeletal phenotype, replicated across both single and double mutants with rigorous genetic epistasis\",\n      \"pmids\": [\"7828847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"HOXB6 overexpression in murine bone marrow expands hematopoietic stem cells and myeloid precursors while inhibiting erythropoiesis and lymphopoiesis, immortalizes a myelomonocytic precursor in vitro, and causes acute myeloid leukemia in vivo. These effects are largely dependent on DNA binding but independent of direct interaction with PBX1 co-factor. Co-expression of MEIS1 dramatically accelerates AML onset.\",\n      \"method\": \"Retrovirus-mediated gene transfer into murine bone marrow; structure-function analysis with DNA-binding and PBX1-interaction mutants; in vivo transplantation; clonogenic assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss/gain of function with defined hematopoietic phenotypes, structure-function mutagenesis, and cooperative interaction with MEIS1 in single study\",\n      \"pmids\": [\"15522959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"HOXB6 represses alpha- and gamma-globin mRNA levels in a DNA-binding-dependent manner. HOXB6 protein co-precipitates endogenous CBP (CREB-binding protein) from nuclear and cytoplasmic compartments of transfected K562 cells and from murine fetal liver cells. The CBP interaction is localized to the homeodomain but does not require helix 3. PBX co-factor interaction is not required for HOXB6 biological activity in this model.\",\n      \"method\": \"Stable transfection of K562 cells; RT-PCR for globin transcripts; co-immunoprecipitation of endogenous CBP with exogenous and endogenous HOXB6; homeodomain deletion/mutation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP of endogenous proteins plus structure-function mutagenesis with defined transcriptional readout\",\n      \"pmids\": [\"15269212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"HOXB6 protein undergoes a change in subcellular localization during epidermal development: it is cytoplasmic in fetal epidermis but substantially nuclear in adult skin. A truncated HOXB6 isoform lacking the homeodomain is expressed in undifferentiated keratinocytes and is largely cytoplasmic, while full-length HOXB6 localizes to the nucleus. Nuclear HOXB6 in adult skin does not co-localize with PBX proteins, suggesting PBX-independent nuclear function.\",\n      \"method\": \"Immunohistochemistry; Western blot; GFP-fusion protein localization in live cells; RNA analysis of isoforms\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — direct localization by IHC and GFP fusion with functional isoform correlation, single lab\",\n      \"pmids\": [\"10906782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"HOXB6 (Hoxb-6) is phosphorylated in vivo at serine-214 by casein kinase II (CK-II). This phosphorylation site is conserved across species. Hoxb-6 is also phosphorylated in vitro by cAMP-dependent protein kinase. The same CK-II phosphopeptide detected in vitro is phosphorylated in embryonic mouse spinal cord in vivo.\",\n      \"method\": \"Baculovirus expression in Sf9 cells; in vitro kinase assays with purified CK-II and PKA; two-dimensional tryptic phosphopeptide mapping; immunoprecipitation from mouse embryonic spinal cords\",\n      \"journal\": \"The Journal of experimental zoology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay plus in vivo phosphopeptide mapping confirming same site\",\n      \"pmids\": [\"10327653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The linker region (LR) connecting the Hoxb6 homeodomain and the hexapeptide is essential for rib-promoting activity in mice. LR-defective Hoxb6 can still bind a target enhancer together with Pax3 but acts as a dominant negative, indicating the LR recruits additional regulatory factors to target DNA. Hoxb6 also regulates somitogenesis by dysregulating Lfng expression in a manner independent of its rib-promoting activity.\",\n      \"method\": \"Transgenic mice expressing LR-deletion mutant HOXB6; ChIP/enhancer binding assays showing Hoxb6-Pax3 co-occupancy; analysis of Lfng expression; skeletal phenotype analysis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mutagenesis with defined skeletal and segmentation phenotypes, dominant-negative mechanism established, multiple orthogonal readouts\",\n      \"pmids\": [\"26718008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Targeted disruption of Hoxb-6 in mice results in an increased number of early erythroid progenitor cells (BFU-E) in bone marrow and fetal liver, while differentiation of other hematopoietic lineages is unaffected. This establishes a role for Hoxb-6 in controlling the generation, proliferation, or survival of erythroid progenitors.\",\n      \"method\": \"Gene targeting in mice; clonogenic progenitor cell assays (colony-forming unit assays for multiple lineages)\",\n      \"journal\": \"American journal of hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with specific hematopoietic cellular phenotype, single lab\",\n      \"pmids\": [\"10996827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Enforced expression of HOXB6 in promyelocytic NB4 cells or myeloblastic HL60 cells inhibits granulocytic or monocytic maturation respectively. HOXB6 expression is transiently induced during normal granulocytopoiesis and monocytopoiesis with an initial induction followed by blockade at early maturation, indicating that regulated HOXB6 expression is required for normal myeloid differentiation.\",\n      \"method\": \"Retroviral overexpression in NB4 and HL60 cell lines; differentiation assays with morphological and molecular readouts\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — gain-of-function with defined differentiation phenotype in two cell line models, single lab\",\n      \"pmids\": [\"12094253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Three distinct cis-regulatory elements govern Hoxb-6 expression: a limb/lateral plate mesoderm (LPM) enhancer directing expression to limb buds and ventro-lateral mesenchyme, an element for ventral spinal cord expression, and an element for mesonephric structures. The limb/LPM element functions as an orientation- and promoter-independent enhancer.\",\n      \"method\": \"Transgenic mouse embryos carrying LacZ reporter gene fused to different Hoxb-6 genomic fragments; 13.2 kb genomic region systematically analyzed\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic transgenic reporter dissection, single lab, multiple constructs\",\n      \"pmids\": [\"8104549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HOXB6 is a direct transcriptional repressor of Sox9: HOXB6 protein binds to the Sox9 promoter and inhibits Sox9 expression. In liver injury, miR-126 suppresses HOXB6 translation, relieving Sox9 repression and enabling SOX9+ liver progenitor cell proliferation and differentiation.\",\n      \"method\": \"Luciferase reporter assay with Sox9 promoter; chromatin immunoprecipitation (ChIP) showing HOXB6 binding to Sox9 promoter; miR-126 target validation; CCl4 liver injury model\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrating direct promoter binding plus functional miRNA-mediated regulation with in vivo model, single lab\",\n      \"pmids\": [\"32763157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Hoxb6 controls multiple independent aspects of skeletal patterning at the cervico-thoracic junction, and its function is subject to modulation by genetic background, establishing Hox-controlled skeletal pattern as a quantitative trait with gene-gene interactions.\",\n      \"method\": \"Hoxb6 knockout mice on multiple genetic backgrounds; quantitative skeletal phenotyping\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with quantitative phenotypic analysis across genetic backgrounds, single lab\",\n      \"pmids\": [\"26800342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of HOXB6 in pancreatic cancer cells inhibits cell proliferation, induces apoptosis and senescence, enhances gemcitabine sensitivity, and affects transcription of immune response pathways, resulting in increased sensitivity to macrophage anti-tumorigenic activity.\",\n      \"method\": \"siRNA/shRNA knockdown in PDAC cell lines; proliferation, apoptosis, and senescence assays; transcriptomic analysis; co-culture with macrophages; drug sensitivity assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — KD with cellular phenotypes but no direct molecular mechanism established, preprint not peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.09.06.611619\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"HOXB6 is a homeodomain transcription factor that binds DNA (requiring an intact homeodomain and linker region), is phosphorylated at Ser-214 by casein kinase II in vivo, physically interacts with CBP/p300 histone acetyltransferase via its homeodomain to repress target genes (including globins), cooperates genetically with adjacent HOXB5 and with MEIS1 in a PBX1-independent manner to control hematopoietic stem cell expansion and myeloid differentiation, specifies cervicothoracic vertebral identity and rib formation through LR-domain-dependent recruitment of regulatory cofactors (including Pax3) to target enhancers, controls erythroid progenitor numbers in the bone marrow, directly represses Sox9 transcription in the liver, and undergoes differentiation-dependent isoform switching and nuclear/cytoplasmic relocalization in epithelial tissues.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"HOXB6 is a homeodomain transcription factor that specifies cervicothoracic vertebral identity, controls rib formation, and regulates hematopoietic lineage decisions. Targeted disruption in mice causes anteriorizing vertebral transformations and rib defects through a mechanism requiring its linker region for cofactor recruitment (including Pax3) to target enhancers, while genetic cooperation with HOXB5 establishes cervicothoracic identity [PMID:7828847, PMID:26718008]. HOXB6 physically interacts with CBP/p300 via its homeodomain to repress globin gene transcription, directly represses Sox9 by binding its promoter, and restrains erythroid progenitor expansion in bone marrow, while its overexpression expands hematopoietic stem cells and cooperates with MEIS1 to induce acute myeloid leukemia in a DNA-binding-dependent but PBX1-independent manner [PMID:15269212, PMID:15522959, PMID:10996827, PMID:32763157]. HOXB6 is phosphorylated at Ser-214 by casein kinase II in vivo and undergoes differentiation-dependent isoform switching and nuclear/cytoplasmic relocalization in epithelial tissues [PMID:10327653, PMID:10906782].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Mapping of cis-regulatory elements controlling Hoxb6 expression revealed that distinct enhancers independently drive expression in limb/lateral plate mesoderm, ventral spinal cord, and mesonephros, establishing the modular transcriptional control underlying HOXB6's tissue-specific roles.\",\n      \"evidence\": \"Transgenic LacZ reporter dissection of 13.2 kb Hoxb6 genomic region in mouse embryos\",\n      \"pmids\": [\"8104549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trans-acting factors binding these enhancers were not identified\", \"No connection to downstream target genes\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Gene disruption established that HOXB6 specifies cervicothoracic vertebral identity and cooperates genetically with adjacent HOXB5, resolving the functional contribution of a single posterior HOX gene to axial patterning and demonstrating nonallelic noncomplementation between paralogous HOX genes.\",\n      \"evidence\": \"Targeted knockout mice; trans-heterozygote genetic complementation; skeletal analysis\",\n      \"pmids\": [\"7828847\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream target genes mediating vertebral identity unknown\", \"Mechanism of HOXB5–HOXB6 cooperation at the molecular level not defined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identification of CK-II-mediated phosphorylation at Ser-214 in vivo provided the first post-translational regulatory mechanism for HOXB6, raising the question of how phosphorylation modulates DNA binding or cofactor interactions.\",\n      \"evidence\": \"In vitro kinase assays with purified CK-II; 2D tryptic phosphopeptide mapping from mouse embryonic spinal cord immunoprecipitates\",\n      \"pmids\": [\"10327653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of Ser-214 phosphorylation on transcriptional activity not tested\", \"No phospho-dead mutant phenotype in vivo\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Two studies clarified HOXB6's roles beyond skeletal patterning: knockout mice showed expanded erythroid progenitors in bone marrow, and differentiation-dependent isoform switching with nuclear/cytoplasmic relocalization was documented in skin, establishing HOXB6 as a regulator of both hematopoietic and epithelial differentiation.\",\n      \"evidence\": \"Hoxb6 knockout clonogenic progenitor assays; immunohistochemistry and GFP-fusion localization in keratinocytes\",\n      \"pmids\": [\"10996827\", \"10906782\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Target genes mediating erythroid progenitor control not identified\", \"Mechanism controlling isoform switching unclear\", \"Whether truncated cytoplasmic isoform has independent function not tested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Enforced expression experiments showed HOXB6 blocks granulocytic and monocytic maturation and is transiently induced during normal myelopoiesis, indicating that dynamic HOXB6 expression levels gate myeloid differentiation progression.\",\n      \"evidence\": \"Retroviral overexpression in NB4 and HL60 cells; morphological and molecular differentiation readouts\",\n      \"pmids\": [\"12094253\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional targets in myeloid cells not identified\", \"Loss-of-function in myeloid lineage not performed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Structure-function studies resolved that HOXB6's oncogenic and transcriptional activities require DNA binding but not PBX1 interaction, and that HOXB6 physically engages CBP/p300 through its homeodomain to repress globin genes, while cooperation with MEIS1 accelerates leukemogenesis.\",\n      \"evidence\": \"Retroviral BM transduction with domain mutants and in vivo transplantation; co-IP of endogenous CBP with HOXB6 in K562 and fetal liver cells; globin RT-PCR\",\n      \"pmids\": [\"15522959\", \"15269212\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide direct targets in hematopoietic cells not mapped\", \"How CBP interaction leads to repression rather than activation not mechanistically resolved\", \"Whether MEIS1 and HOXB6 form a physical complex not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The linker region between the homeodomain and hexapeptide was shown to be essential for rib-promoting activity by recruiting additional regulatory cofactors to target enhancers (co-occupied with Pax3), separating HOXB6's rib-patterning function from its role in somitogenesis via Lfng regulation.\",\n      \"evidence\": \"Transgenic mice expressing LR-deletion mutant; ChIP showing Hoxb6-Pax3 co-occupancy; Lfng and skeletal phenotype analysis\",\n      \"pmids\": [\"26718008\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of LR-recruited cofactors unknown\", \"Whether Pax3 interaction is direct or enhancer-mediated not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Quantitative phenotyping across genetic backgrounds showed HOXB6 skeletal functions are modulated by genetic modifiers, establishing Hox-controlled skeletal pattern as a quantitative trait.\",\n      \"evidence\": \"Hoxb6 knockout mice on multiple inbred backgrounds; quantitative skeletal scoring\",\n      \"pmids\": [\"26800342\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Modifier loci not mapped\", \"Molecular basis of background sensitivity unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"HOXB6 was identified as a direct transcriptional repressor of Sox9 in the liver, with miR-126-mediated translational suppression of HOXB6 enabling SOX9+ progenitor activation during liver injury, linking HOXB6 to adult tissue regeneration.\",\n      \"evidence\": \"ChIP showing HOXB6 binding at Sox9 promoter; luciferase reporters; miR-126 target validation; CCl4 liver injury model\",\n      \"pmids\": [\"32763157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HOXB6 represses Sox9 in other tissues not tested\", \"Additional HOXB6 target genes in liver not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the genome-wide direct target repertoire of HOXB6 in hematopoietic and skeletal contexts, the identity of linker-region-recruited cofactors essential for rib formation, the functional consequence of CK-II phosphorylation, and how HOXB6–CBP interaction mediates transcriptional repression rather than activation.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No genome-wide ChIP-seq or CUT&RUN target map in any tissue\", \"No structural model of HOXB6–CBP or HOXB6–cofactor complexes\", \"Functional role of Ser-214 phosphorylation untested by mutagenesis in vivo\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1, 2, 5, 9]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 7, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 3, 9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0074160\", \"supporting_discovery_ids\": [1, 2, 5, 7, 9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 5, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CBP\", \"HOXB5\", \"MEIS1\", \"PAX3\"],\n    \"other_free_text\": []\n  }\n}\n```"}