{"gene":"HOXA10","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1995,"finding":"Targeted knockout of Hoxa10 in mice causes anterior homeotic transformation of lumbar vertebrae, bilateral cryptorchidism with spermatogenesis defects in males, and uterine-factor embryonic lethality in ~80% of females between days 2.5-3.5 post coitum, coinciding with maternal Hoxa10 expression in distal oviductal and uterine epithelium, establishing a direct role for Hoxa10 in male and female fertility.","method":"Targeted gene knockout in mice, phenotypic analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function mouse model with specific phenotypic readouts, foundational study replicated across the field","pmids":["7700356"],"is_preprint":false},{"year":2000,"finding":"Maternal Hoxa10 expression in the uterus is required for embryo implantation; antisense oligonucleotide suppression of Hoxa10 before implantation significantly decreased implantation sites, while constitutive Hoxa10 expression increased litter size.","method":"In vivo uterine liposome-mediated gene transfection with antisense oligonucleotides or expression plasmid in pregnant mice; implantation site counting","journal":"Gene therapy","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct gain- and loss-of-function in vivo with quantitative implantation readout, replicated concept across multiple papers","pmids":["10981664"],"is_preprint":false},{"year":2002,"finding":"HOXA10 protein interacts with and is repressed by SHP1 protein-tyrosine phosphatase in undifferentiated myeloid cells; SHP1 dephosphorylates tyrosine residues in the conserved HOXA10 homeodomain, increasing HoxA10 DNA binding affinity and transcriptional repression of target genes CYBB (gp91PHOX) and NCF2 (p67PHOX).","method":"Co-immunoprecipitation of SHP1 with HoxA10; phosphotyrosine analysis; transcriptional reporter assays; EMSA; tyrosine phosphorylation mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (Co-IP, mutagenesis, in vitro binding, reporter assays) in a single focused study","pmids":["12145285"],"is_preprint":false},{"year":2003,"finding":"HoxA10 represses transcription of CYBB (gp91PHOX) and NCF2 (p67PHOX) in undifferentiated myeloid cells through a Pbx1-independent repression domain (amino acids 224–249) that recruits histone deacetylase 2 (HDAC2); HDAC inhibitors abrogate this repression.","method":"Domain deletion/mutagenesis; co-immunoprecipitation of HOXA10 with HDAC2; HDAC inhibitor treatment; transcriptional reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis identified repression domain, Co-IP confirmed HDAC2 interaction, functional inhibitor experiments, multiple orthogonal methods","pmids":["14512427"],"is_preprint":false},{"year":2005,"finding":"HoxA10 represses NCF2 (p67PHOX) transcription via a homologous cis-element in the NCF2 promoter in a tyrosine phosphorylation- and histone deacetylase-dependent manner, paralleling its repression of CYBB; IFN-γ-induced tyrosine phosphorylation of the HoxA10 homeodomain decreases binding to this element and abrogates repression.","method":"Reporter assays with NCF2 promoter constructs; EMSA; IFN-γ treatment; HDAC inhibitor experiments; tyrosine phosphorylation analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal biochemical methods, mechanistic mutagenesis, replicated parallel mechanism from prior CYBB study","pmids":["16210632"],"is_preprint":false},{"year":2006,"finding":"SHP2 protein-tyrosine phosphatase dephosphorylates HoxA10 in undifferentiated myeloid cells, maintaining HoxA10 in a DNA-binding-competent state that represses CYBB and NCF2 transcription; constitutively active SHP2 mutants (found in human AML) sustain HoxA10 dephosphorylation throughout myelopoiesis, persistently repressing myeloid differentiation genes.","method":"Co-immunoprecipitation of SHP2 with HoxA10; phosphotyrosine Western blot; transcriptional reporter assays; expression of constitutively active SHP2 mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, phosphorylation analysis, reporter assays, disease-relevant mutant validation in single focused study","pmids":["17138561"],"is_preprint":false},{"year":2006,"finding":"Bisphenol A (BPA) drives HOXA10 expression through the HOXA10 estrogen response element (ERE) and indirectly through an autoregulatory element (ARE); BPA-induced HOXA10 upregulation via ERE is blocked by ER antagonist ICI, while ARE induction requires ER signaling and HOXA10 itself; in utero BPA exposure imprints lasting stromal HOXA10 overexpression uncoupled from estrogen stimulation in adult mice.","method":"Luciferase reporter assays with HOXA10-ERE and ARE constructs; ER antagonist ICI treatment; in vivo in utero BPA exposure; RT-PCR in 2- and 6-week-old offspring","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays with defined elements plus in vivo imprinting experiment, single lab","pmids":["17093138"],"is_preprint":false},{"year":2007,"finding":"HOXA10 activates the Runx2 P1 promoter via a functional Hox core motif to induce osteoblast differentiation; HOXA10 also directly activates alkaline phosphatase, osteocalcin, and bone sialoprotein gene promoters; HOXA10 mediates chromatin hyperacetylation and H3K4 trimethylation at these loci; HOXA10 can induce osteoblast genes in Runx2-null cells, establishing a direct Runx2-independent pathway.","method":"ChIP; promoter reporter assays; siRNA knockdown; exogenous expression; analysis in Runx2-null cells; histone modification analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (ChIP, reporter assays, KD/OE, Runx2-null rescue), single rigorous study","pmids":["17325044"],"is_preprint":false},{"year":2007,"finding":"HOXA10 negatively regulates IGFBP1 mRNA expression in decidualizing human endometrial stromal cells (HSC); overexpression of HOXA10 in HSC decreased IGFBP1 mRNA, while HOXA10 silencing increased IGFBP1 mRNA even in the presence of decidualization stimuli.","method":"HOXA10 overexpression and siRNA knockdown in human endometrial stromal cells; RT-PCR for IGFBP1","journal":"Molecular human reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain- and loss-of-function with defined molecular readout, single lab","pmids":["17350963"],"is_preprint":false},{"year":2004,"finding":"HOXA10 expression in ER-negative BT20 breast cancer cells increases p53 protein expression and reduces invasiveness through Matrigel; estradiol and tamoxifen increase HOXA10 mRNA in ER-positive MCF-7 cells.","method":"Constitutive HOXA10 expression in BT20 cells; Matrigel invasion assay; Western blot for p53; RT-PCR/Northern blot for HOXA10","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, single method per readout, but direct gain-of-function with two orthogonal phenotypic readouts","pmids":["15044858"],"is_preprint":false},{"year":2006,"finding":"HOXA10 inhibits invasive behavior of endometrial carcinoma cells and tumor dissemination by inducing E-cadherin expression through downregulation of the E-cadherin repressor Snail, thereby suppressing epithelial-mesenchymal transition.","method":"Enforced HOXA10 expression in endometrial carcinoma cells; Matrigel invasion assay; nude mouse xenograft; Western blot/RT-PCR for Snail and E-cadherin","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function in vitro and in vivo, defined molecular pathway (Snail/E-cadherin), single lab","pmids":["16424022"],"is_preprint":false},{"year":2008,"finding":"Constitutively active SHP2 cooperates with HoxA10 overexpression to accelerate AML progression in mice; HoxA10 activates transcription of DUSP4 (encoding anti-apoptotic Mkp2) in myeloid progenitors, and SHP2-mediated dephosphorylation of HoxA10 maintains DUSP4 activation and CYBB/NCF2 repression throughout myelopoiesis.","method":"Murine bone marrow transplantation with HoxA10 overexpression and constitutively active SHP2; reporter assays; ChIP; phosphorylation analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo bone marrow model plus biochemical experiments, single lab","pmids":["19022774"],"is_preprint":false},{"year":2010,"finding":"Pbx1 negatively regulates Hoxa10-mediated transcription at osteoblast gene promoters (osteocalcin, bone sialoprotein) by associating with histone deacetylases and maintaining H3K9 methylation; during differentiation, Pbx1 dissociates from these promoters allowing Hoxa10 to recruit CBP/p300, increase histone acetylation, and decrease H3K9 methylation to activate transcription.","method":"ChIP; shRNA knockdown of Pbx1; wild-type and mutated promoter reporter assays; histone modification analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ChIP, promoter mutagenesis, shRNA KD, multiple histone modification readouts in one study","pmids":["20439491"],"is_preprint":false},{"year":2010,"finding":"HOXA10 directly represses KLF9 expression specifically in endometrial epithelial cells (not stromal cells) by binding to the KLF9 promoter; EMSA confirmed direct HOXA10–KLF9 promoter binding; targeted mutation of the HOXA10-binding site abolished repression.","method":"Transient transfection of HOXA10; reporter assays with KLF9 promoter; EMSA; targeted promoter mutation; immunohistochemistry","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 1 / Moderate — EMSA + promoter mutagenesis + reporter assays + cell-type specificity demonstrated, single lab","pmids":["20463357"],"is_preprint":false},{"year":2011,"finding":"miR-135a and miR-135b directly suppress HOXA10 expression by binding the HOXA10 3' UTR in endometrial stromal cells (cell-type specific; absent in MCF-7 cells); transfection with miR-135a/b or their inhibitors reciprocally altered HOXA10 mRNA and protein; luciferase reporter confirmed binding site.","method":"miRNA transfection; luciferase reporter with HOXA10 3' UTR; qPCR; Western blot; endometrial biopsy qPCR","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase + reciprocal gain/loss of function, cell-type specificity control, single lab","pmids":["21956427"],"is_preprint":false},{"year":2011,"finding":"HoxA10 activates transcription of ARIH2 (encoding the E3 ubiquitin ligase Triad1) via two distinct HoxA10-binding cis elements in the ARIH2 promoter in myeloid cells; HoxA10-overexpressing myeloid cells show a Triad1-dependent increase in protein ubiquitination.","method":"Reporter assays with ARIH2 promoter cis elements; ChIP; Western blot for ubiquitination; Triad1 knockdown rescue experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ChIP, promoter reporter assays, knockdown rescue, ubiquitination functional assay, multiple orthogonal methods","pmids":["21454682"],"is_preprint":false},{"year":2011,"finding":"HoxA10 activates CDX4 transcription via a cis element in the CDX4 promoter; Cdx4 in turn activates the HOXA10 promoter via a Cdx4-binding cis element, forming a positive feedback loop; CDX4 knockdown decreases cytokine hypersensitivity in HoxA10-overexpressing myeloid progenitors.","method":"Reporter assays with CDX4 and HOXA10 promoter cis elements; ChIP; knockdown experiments; cytokine proliferation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ChIP, bidirectional promoter reporter assays, knockdown, functional cytokine assays in single focused study","pmids":["21471217"],"is_preprint":false},{"year":2012,"finding":"HoxA10 activates Fgf2 transcription via two cis elements in the FGF2 proximal promoter in myeloid cells, increasing Fgf2 secretion; autocrine Fgf2 activates a PI3K-dependent increase in β-catenin, stimulating myeloid progenitor proliferation and cytokine hypersensitivity.","method":"Reporter assays with FGF2 promoter cis elements; ChIP; Fgf2 secretion ELISA; PI3K inhibitor treatment; β-catenin Western blot; proliferation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ChIP, promoter reporter assays, secretion measurement, pharmacological inhibition, downstream signaling validation, multiple orthogonal methods","pmids":["22493287"],"is_preprint":false},{"year":2012,"finding":"β-Catenin directly activates HOXA10 and CDX4 transcription via novel cis elements in their promoters in myeloid progenitor cells; HoxA10-induced Fgf2 production activates β-catenin in an autocrine manner, which then further amplifies HOXA10 and CDX4 expression.","method":"Reporter assays; ChIP for β-catenin at HOXA10 and CDX4 promoters; Fgf2 neutralization; β-catenin knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ChIP at defined cis elements, promoter reporter assays, signaling perturbation, multiple orthogonal methods","pmids":["23038246"],"is_preprint":false},{"year":2013,"finding":"PCAF acetyltransferase physically interacts with HOXA10 and acetylates it at lysines K338 and K339, impairing HOXA10-mediated transcription of ITGB3 (β3-integrin) and reducing embryo adhesiveness in endometrial epithelial cells.","method":"Co-immunoprecipitation; confocal immunofluorescence; luciferase reporter; ChIP; Western blot; BeWo spheroid attachment assay; siRNA knockdown/overexpression of PCAF","journal":"The Journal of clinical endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — Co-IP, site-specific acetylation mapping (K338/K339), reporter assays, ChIP, functional adhesion assay, multiple orthogonal methods","pmids":["24037888"],"is_preprint":false},{"year":2012,"finding":"HOXA10 regulates FKBP4 (FKBP52) expression in human endometrial stromal cells; overexpression of HOXA10 increased FKBP4 mRNA and protein, while HOXA10 knockdown decreased FKBP4 expression and impaired decidualization.","method":"HOXA10 overexpression and siRNA knockdown in HESCs; qRT-PCR; Western blot; decidualization markers (IGFBP1)","journal":"Reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss of function, single lab, two orthogonal methods","pmids":["22279148"],"is_preprint":false},{"year":2008,"finding":"HOXA10 directly regulates Calpain5 expression in endometrial cells; transfection with HOXA10 expression construct increased Calpain5 mRNA, while HOXA10 siRNA decreased Calpain5 expression, suggesting HOXA10 promotes apoptosis resistance via a Calpain5/caspase pathway.","method":"HOXA10 overexpression and siRNA in HESC cells; qRT-PCR; immunohistochemistry","journal":"Molecular human reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — reciprocal gain/loss of function, single lab, single readout method","pmids":["18829447"],"is_preprint":false},{"year":2010,"finding":"HOXA10 controls hematopoietic stem cell self-renewal and repopulating capacity in a dose-dependent manner; intermediate HOXA10 levels expand HSCs ~15-fold after in vitro culture, while high levels block erythroid and megakaryocyte development; downstream targets include HLF, Dkk-1, Gfi-1, and Gata-1, with HOXA10 binding sites confirmed in HLF, Dkk-1, and Gata-1, and transcriptional activation of Dkk-1 and Gfi-1 demonstrated.","method":"Doxycycline-inducible transgenic mice; bone marrow repopulation assays; gene expression profiling; HOXA10 binding site analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — inducible in vivo model with dose-dependent phenotype, downstream gene activation confirmed, single rigorous study","pmids":["17234739"],"is_preprint":false},{"year":2015,"finding":"HoxA10 terminates emergency granulopoiesis by activating ARIH2 (Triad1) transcription during myeloid differentiation; HOXA10-knockout mice exhibit overwhelming fatal emergency granulopoiesis reversed by re-expression of Triad1 in bone marrow; HoxA9 antagonizes this by repressing ARIH2 transcription; differentiation-stage-specific ARIH2 transcription is regulated by tyrosine phosphorylation states of HoxA9 and HoxA10.","method":"HOXA10 knockout mice; bone marrow Triad1 re-expression rescue; ARIH2 knockout mice; reporter assays; phosphorylation analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO with rescue, genetic epistasis between HoxA9 and HoxA10, multiple orthogonal methods","pmids":["25895533"],"is_preprint":false},{"year":2017,"finding":"Downregulation of HOXA10 in decidual cells after embryo implantation promotes trophoblast invasion by increasing LIF and IL-6 secretion, which activates STAT3 (Tyr705) in trophoblast cells, upregulating MMP activity and decreasing TIMPs; STAT3 knockdown in trophoblasts rescues the invasion mediated by HOXA10-depleted decidual cells.","method":"HOXA10 siRNA depletion of decidual cells; conditioned medium trophoblast invasion assay; MMP activity assay; STAT3 knockdown; Western blot for phospho-STAT3; ELISA for LIF and IL-6","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (conditioned medium assay, STAT3 rescue, MMP assay, cytokine ELISA), defined paracrine pathway","pmids":["28520923"],"is_preprint":false},{"year":2020,"finding":"MEIS1 physically interacts with HOXA10 in human endometrial stromal cells; the MEIS1-HOXA10 complex binds the promoters of KAT2B and ETA and regulates their transcriptional activity; MEIS1 deficiency (siRNA and CRISPR-Cas9) impairs decidualization, and KAT2B/ETA overexpression partially rescues decidualization defects in MEIS1-knockout cells.","method":"Co-immunoprecipitation of MEIS1 with HOXA10; siRNA and CRISPR-Cas9 MEIS1 knockout; luciferase reporter; ChIP for MEIS1-HOXA10 at KAT2B and ETA promoters; rescue overexpression","journal":"Journal of molecular endocrinology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — Co-IP, ChIP, promoter reporter, CRISPR KO, functional rescue, multiple orthogonal methods in single study","pmids":["32197234"],"is_preprint":false},{"year":2021,"finding":"Hoxa10 is required for genomic stability and mitotic function in somite-derived satellite cells; satellite cell-specific Hoxa10 ablation in mice causes genomic instability, mitotic catastrophe, and impaired regeneration specifically of somite-derived muscles (not cranial mesoderm-derived muscles), establishing Hoxa10 as a positional memory gene in adult muscle stem cells.","method":"Satellite cell-specific conditional Hoxa10 knockout mice; muscle regeneration assays; DNA methylation analysis of Hox-A locus; immunofluorescence for mitotic markers","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with tissue-specific phenotype and molecular mechanism (genomic instability, mitotic catastrophe), lineage-specific control","pmids":["34108202"],"is_preprint":false},{"year":2021,"finding":"HOXA10 acts as an upstream transcription factor for ALKBH5 and forms a regulatory loop with it; the ALKBH5-HOXA10 loop activates the JAK2/STAT3 signaling pathway by mediating ALKBH5-dependent m6A demethylation of JAK2 mRNA, promoting cisplatin resistance in epithelial ovarian cancer cells.","method":"MeRIP-seq; RNA-seq; ChIP; RNA immunoprecipitation; luciferase reporter; in vitro and in vivo functional assays; ALKBH5/HOXA10 knockdown","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — MeRIP-seq for m6A mapping, ChIP for HOXA10 at ALKBH5 promoter, RIP, reporter assay, in vivo rescue, multiple orthogonal methods","pmids":["34496932"],"is_preprint":false},{"year":2021,"finding":"HOXA10 promotes gastric cancer EMT and metastasis by binding the TGFB2 promoter, activating TGFB2 transcription and secretion, triggering TGFβ/Smad signaling with Smad2/3 nuclear translocation; the downstream Smad proteins mediate METTL3 expression (confirmed by CoIP and ChIP), and METTL3 elevates overall m6A levels to drive EMT.","method":"ChIP-qPCR for HOXA10 at TGFB2 promoter; dual-luciferase reporter; CoIP of Smad proteins with METTL3; colorimetric m6A assay; in vivo lung metastasis models; rescue experiments","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ChIP, CoIP, reporter assay, m6A assay, in vivo rescue, multiple orthogonal methods","pmids":["33563300"],"is_preprint":false},{"year":2019,"finding":"HOXA10 binds the BCL2 promoter region and induces BCL2 expression, thereby inhibiting the intrinsic apoptosis pathway and promoting gastric cancer cell proliferation.","method":"ChIP-qPCR for HOXA10 at BCL2 promoter; qRT-PCR; Western blot; rescue experiments; in vivo xenograft","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR with rescue experiment, single lab","pmids":["31364281"],"is_preprint":false},{"year":2019,"finding":"HOXA10 knockdown in hepatocellular carcinoma cells suppresses HDAC1 transcription (via direct HOXA10 binding to HDAC1 promoter confirmed by ChIP and luciferase assay), leading to increased p53 acetylation at Lys382, cell cycle arrest, and apoptosis; HDAC1 overexpression reverses the effects of HOXA10 knockdown.","method":"siRNA knockdown; ChIP and luciferase reporter for HOXA10 at HDAC1 promoter; flow cytometry; Western blot for p53 acetylation; in vivo xenograft; rescue experiments","journal":"Cancer management and research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ChIP, promoter reporter, p53 acetylation site-specific analysis, rescue experiments, multiple orthogonal methods","pmids":["31440094"],"is_preprint":false},{"year":2021,"finding":"HOXA10 promotes HDAC1 expression in lung adenocarcinoma; HDAC1 deacetylates DNMT1 to stabilize it, and DNMT1 methylates the KLF4 promoter to silence KLF4, creating a HOXA10/HDAC1/DNMT1/KLF4 axis that drives LAD proliferation and migration; CoIP confirmed HDAC1-DNMT1 interaction.","method":"ChIP; dual luciferase assay; CoIP of HDAC1 with DNMT1; siRNA/shRNA depletion; Western blot; in vivo xenograft","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ChIP, CoIP, luciferase, methylation analysis, in vivo rescue, multiple orthogonal methods in single study","pmids":["33596966"],"is_preprint":false},{"year":2022,"finding":"HOXA10 directly binds a conserved motif (TGTACTAAAAA) in the E-cadherin promoter to activate E-cadherin expression, improving endometrial receptivity and embryo adhesion; siRNA knockdown of HOXA10 in mice reduced implantation and live birth rates.","method":"ChIP for HOXA10 at E-cadherin promoter; dual luciferase reporter; siRNA and overexpression transfection; JEG-3 spheroid attachment assay; in vivo HOXA10 siRNA mouse model","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ChIP, promoter motif mutagenesis, reporter assay, in vitro adhesion assay, and in vivo mouse model in a single study","pmids":["35044439"],"is_preprint":false},{"year":2014,"finding":"HOXA10 directly binds the ZIC2 promoter and upregulates ZIC2 transcription in nasopharyngeal carcinoma cells; luciferase reporters with truncated ZIC2 promoter sequences confirmed the HOXA10 binding site; ZIC2 knockdown reverses HOXA10-induced proliferation and invasion.","method":"ChIP; luciferase reporters with truncated ZIC2 promoter; HOXA10 overexpression; ZIC2 siRNA rescue","journal":"European review for medical and pharmacological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and promoter reporter assays with truncation mapping, rescue experiment, single lab","pmids":["28338202"],"is_preprint":false},{"year":2014,"finding":"HOXA10 promotes pancreatic cancer cell invasion and MMP-3 expression via TGFβ2-mediated activation of the p38 MAPK pathway; HOXA10 knockdown decreases TGFβ2 and MMP-3 expression and suppresses p38 activation; TGFβ2 neutralization or p38 inhibition blocks HOXA10-mediated invasion.","method":"siRNA knockdown; overexpression; TGFβ2 neutralizing antibody; p38 inhibitor (SB239063); invasion assays; Western blot","journal":"Digestive diseases and sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and antibody interventions plus reciprocal KD/OE, defined pathway, single lab","pmids":["24464212"],"is_preprint":false},{"year":2015,"finding":"CTCF binds a 20 bp motif in the HOXA10 core promoter region and negatively regulates HOXA10 expression in breast cancer cells by maintaining H3K27me3 inactivation marks at the HOXA10 promoter; in silico and in vitro mutation assays confirmed the CTCF binding site.","method":"ChIP for CTCF and H3K27me3 at HOXA10 promoter; promoter reporter assay; in silico binding site prediction; mutation assay; CTCF overexpression and knockdown","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, promoter reporter, site mutagenesis, histone modification analysis, single lab","pmids":["26478432"],"is_preprint":false},{"year":2020,"finding":"HOXA10 inhibits osteogenic differentiation of periodontal ligament stem cells by increasing DKK1 expression and reducing nuclear β-catenin accumulation; HOXA10 overexpression reduces nuclear β-catenin and increases DKK1; effects are rescued by Wnt/β-catenin activator LiCl, and HOXA10 knockdown effects are antagonized by Wnt inhibitor ICG-001.","method":"HOXA10 overexpression and knockdown in hPDLSCs; ALP and Alizarin Red staining; Western blot for nuclear β-catenin and DKK1; LiCl and ICG-001 treatment","journal":"Connective tissue research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological rescue with both activator and inhibitor, reciprocal gain/loss of function, multiple readouts, single lab","pmids":["32299243"],"is_preprint":false},{"year":2022,"finding":"LncRNA NEAT1 binds CTCF and recruits it to the HOXA10 promoter; CTCF binding downregulates HOXA10 gene expression by regulating histone modification levels; the lncRNA NEAT1/CTCF/HOXA10 signaling pathway regulates endometrial epithelial cell proliferation and endometrial receptivity establishment.","method":"RNA immunoprecipitation; ChIP; histone modification analysis; in vitro and in vivo knockdown models; trophoblast attachment assay","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and ChIP confirm physical interactions, histone modification readout, functional rescue, single lab","pmids":["35574918"],"is_preprint":false},{"year":2010,"finding":"EZH2 (component of Polycomb Repressor Complex 2, PRC2) represses HOXA10 expression in T-cell lines; siRNA knockdown of EZH2 in JURKAT cells enhanced HOXA10 expression, and DZNep (EZH2/PRC2 inhibitor) treatment elevated HOXA10 expression; HOXA10 and HOXA9 directly activated ID2 expression (ChIP and promoter analysis).","method":"siRNA knockdown of EZH2; DZNep pharmacological inhibition; ChIP; promoter reporter; overexpression","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological EZH2 inhibition, ChIP, reporter assay, single lab","pmids":["20565746"],"is_preprint":false}],"current_model":"HOXA10 is a homeodomain transcription factor that activates or represses target gene promoters through direct DNA binding; its activity is regulated by tyrosine phosphorylation (reducing DNA binding affinity, mediated by IFN-γ signaling and reversed by SHP1/SHP2 phosphatases), acetylation by PCAF (at K338/K339, impairing transcriptional activation), and by co-factor complexes (Pbx1 recruiting HDACs to repress, Meis1 enhancing activity); in myeloid cells HOXA10 represses phagocyte oxidase genes (CYBB, NCF2) via HDAC2 recruitment and activates FGF2, CDX4, ARIH2/Triad1, and DUSP4 to control progenitor expansion, differentiation, and emergency granulopoiesis; in endometrium HOXA10 directly activates ITGB3 and E-cadherin promoters and represses KLF9 and IGFBP1, regulating implantation and decidualization via co-factors including MEIS1; in bone, HOXA10 activates Runx2, alkaline phosphatase, osteocalcin, and bone sialoprotein through chromatin hyperacetylation and H3K4 trimethylation; in various cancers HOXA10 drives EMT via TGFB2/Smad/METTL3 signaling, activates BCL2 and HDAC1 (the latter suppressing KLF4 via DNMT1-mediated methylation), and acts upstream of the ALKBH5/JAK2(m6A)/STAT3 cisplatin-resistance axis."},"narrative":{"mechanistic_narrative":"HOXA10 is a homeodomain transcription factor that establishes positional identity and orchestrates lineage-specific differentiation programs, with foundational genetic evidence linking it to skeletal patterning, male and female fertility, and embryo implantation [PMID:7700356, PMID:10981664]. It acts as a sequence-specific DNA-binding regulator that can either activate or repress target promoters depending on cofactor context and post-translational state. Its DNA-binding activity is controlled by tyrosine phosphorylation of the homeodomain: the phosphatases SHP1 and SHP2 dephosphorylate HOXA10 to sustain a DNA-binding-competent repressor state, while IFN-γ-induced phosphorylation lowers affinity and relieves repression [PMID:12145285, PMID:17138561, PMID:16210632]. PCAF acetylates HOXA10 at K338/K339 to impair its transcriptional activation of targets such as ITGB3 [PMID:24037888]. In myeloid progenitors, HOXA10 represses the phagocyte oxidase genes CYBB and NCF2 by recruiting HDAC2 through a Pbx1-independent repression domain, while activating FGF2, CDX4, ARIH2/Triad1, and DUSP4 to drive progenitor expansion, autocrine FGF2/PI3K/β-catenin signaling, and the timely termination of emergency granulopoiesis [PMID:14512427, PMID:21454682, PMID:21471217, PMID:22493287, PMID:23038246, PMID:25895533], and it governs hematopoietic stem cell self-renewal in a dose-dependent manner [PMID:17234739]. In endometrium, HOXA10 directly activates ITGB3 and E-cadherin and represses KLF9 and IGFBP1, working with the cofactor MEIS1 to regulate receptivity, implantation, and decidualization [PMID:20463357, PMID:24037888, PMID:35044439, PMID:32197234, PMID:17350963]. In osteoblast differentiation it activates Runx2, alkaline phosphatase, osteocalcin, and bone sialoprotein through chromatin hyperacetylation and H3K4 trimethylation, with Pbx1 switching the locus between HDAC-mediated repression and CBP/p300-mediated activation [PMID:17325044, PMID:20439491]. In cancers, HOXA10 promotes EMT, proliferation, and chemoresistance by activating TGFB2/Smad/METTL3 m6A signaling, BCL2, HDAC1 (suppressing KLF4 via DNMT1 methylation), and an ALKBH5/JAK2-m6A/STAT3 cisplatin-resistance loop [PMID:33563300, PMID:31364281, PMID:33596966, PMID:34496932]. HOXA10 is itself controlled by upstream repression via EZH2/PRC2 and CTCF-dependent histone modification and by miR-135a/b targeting its 3' UTR [PMID:20565746, PMID:26478432, PMID:21956427].","teleology":[{"year":1995,"claim":"Established that HOXA10 is required in vivo for axial patterning and reproductive function, defining the biological problem space the protein operates in.","evidence":"Targeted Hoxa10 knockout in mice with phenotypic analysis","pmids":["7700356"],"confidence":"High","gaps":["Does not identify direct transcriptional targets","Tissue-autonomous versus systemic contributions not separated"]},{"year":2000,"claim":"Demonstrated that maternal uterine HOXA10 is functionally required for embryo implantation, converting the knockout phenotype into a manipulable dose-dependent process.","evidence":"In vivo uterine antisense and expression-plasmid transfection with implantation site counting in mice","pmids":["10981664"],"confidence":"High","gaps":["Downstream implantation effectors not defined","Direct DNA targets not identified"]},{"year":2002,"claim":"Defined the first post-translational control of HOXA10, showing tyrosine phosphorylation of the homeodomain governs DNA binding and that SHP1 dephosphorylation enables repression of myeloid oxidase genes.","evidence":"Co-IP, phosphotyrosine mapping, EMSA, and reporter assays in myeloid cells","pmids":["12145285"],"confidence":"High","gaps":["Kinase responsible for phosphorylation not identified here","In vivo relevance to myelopoiesis not yet established"]},{"year":2003,"claim":"Identified the mechanism of HOXA10 repression at oxidase genes as recruitment of HDAC2 via a discrete Pbx1-independent repression domain, mechanistically distinguishing repression from cofactor-dependent activity.","evidence":"Domain mutagenesis, HDAC2 Co-IP, and HDAC inhibitor reporter assays in myeloid cells","pmids":["14512427"],"confidence":"High","gaps":["Other corepressors at these loci not mapped","Structural basis of the repression domain unknown"]},{"year":2005,"claim":"Generalized the phosphorylation-dependent repression model by showing IFN-γ signaling relieves HOXA10 repression of NCF2, linking cytokine signaling to oxidase gene derepression during differentiation.","evidence":"NCF2 promoter reporters, EMSA, IFN-γ treatment, and HDAC inhibitor experiments","pmids":["16210632"],"confidence":"High","gaps":["Identity of IFN-γ-activated tyrosine kinase not defined","Quantitative contribution to differentiation timing unclear"]},{"year":2006,"claim":"Completed the phosphatase regulatory axis and connected it to disease by showing SHP2 sustains HOXA10 dephosphorylation, with leukemia-associated activating SHP2 mutants persistently repressing differentiation genes.","evidence":"Co-IP, phosphorylation analysis, reporter assays, and constitutively active SHP2 mutants in myeloid cells","pmids":["17138561"],"confidence":"High","gaps":["Direct causation in human AML not tested here","Full target set sustained by SHP2 not enumerated"]},{"year":2006,"claim":"Showed HOXA10 expression is hormonally and environmentally regulated through estrogen-response and autoregulatory promoter elements, identifying HOXA10 as a node for endocrine disruptor imprinting.","evidence":"ERE/ARE reporter assays, ER antagonist treatment, and in utero BPA exposure in mice","pmids":["17093138"],"confidence":"Medium","gaps":["Single-lab reporter and imprinting data","Mechanism of persistent estrogen-uncoupled expression not defined"]},{"year":2007,"claim":"Established HOXA10 as a direct activator of the osteoblast differentiation program acting upstream of and parallel to Runx2 through chromatin modification.","evidence":"ChIP, promoter reporters, siRNA, Runx2-null rescue, and histone modification analysis","pmids":["17325044"],"confidence":"High","gaps":["Histone-modifying enzymes recruited not yet identified","Endogenous requirement in bone in vivo not tested"]},{"year":2007,"claim":"Extended HOXA10 transcriptional control into endometrial decidualization by showing it negatively regulates IGFBP1.","evidence":"Reciprocal HOXA10 overexpression/knockdown with RT-PCR in human endometrial stromal cells","pmids":["17350963"],"confidence":"Medium","gaps":["Direct promoter binding to IGFBP1 not shown","Cofactor dependence not defined"]},{"year":2008,"claim":"Linked the phosphatase/HOXA10 axis to leukemogenesis and added DUSP4 as an anti-apoptotic activated target sustaining myeloid progenitor survival.","evidence":"Murine bone marrow transplantation with HoxA10 and active SHP2, ChIP, and reporter assays","pmids":["19022774"],"confidence":"Medium","gaps":["Single-lab in vivo model","Relative contribution of DUSP4 versus oxidase repression to AML not dissected"]},{"year":2008,"claim":"Identified Calpain5 as a HOXA10-regulated gene implicating HOXA10 in endometrial apoptosis resistance.","evidence":"HOXA10 overexpression/siRNA with qRT-PCR and IHC in endometrial cells","pmids":["18829447"],"confidence":"Medium","gaps":["Single readout method","Direct binding to Calpain5 promoter not demonstrated"]},{"year":2010,"claim":"Resolved the molecular switch by which Pbx1 converts HOXA10 from repressor to activator at bone gene promoters via differential corepressor/coactivator recruitment.","evidence":"ChIP, Pbx1 shRNA, promoter mutagenesis, and histone modification analysis","pmids":["20439491"],"confidence":"High","gaps":["Signal triggering Pbx1 dissociation not identified","Generality of switch to non-bone loci untested"]},{"year":2010,"claim":"Demonstrated direct, cell-type-specific repression of KLF9 by HOXA10 binding the KLF9 promoter, refining endometrial epithelial versus stromal target logic.","evidence":"Reporter assays, EMSA, and promoter-site mutation in endometrial cells","pmids":["20463357"],"confidence":"High","gaps":["Basis of epithelial-specific activity not defined","In vivo consequence of KLF9 derepression not tested"]},{"year":2010,"claim":"Established HOXA10 as a dose-dependent regulator of hematopoietic stem cell self-renewal with defined downstream targets.","evidence":"Doxycycline-inducible transgenic mice, repopulation assays, expression profiling, and binding-site analysis (HLF, Dkk-1, Gata-1)","pmids":["17234739"],"confidence":"High","gaps":["Mechanism of dose-dependent lineage block unclear","Direct versus indirect targets incompletely separated"]},{"year":2010,"claim":"Placed HOXA10 within Polycomb-controlled gene regulation, showing EZH2/PRC2 represses HOXA10 and that HOXA10 activates ID2 in lymphoid cells.","evidence":"EZH2 siRNA, DZNep inhibition, ChIP, and reporter assays in T-cell lines","pmids":["20565746"],"confidence":"Medium","gaps":["Single-lineage context","Functional consequence of EZH2-mediated HOXA10 repression not assayed"]},{"year":2011,"claim":"Defined a HOXA10-driven myeloid transcriptional network (ARIH2/Triad1, CDX4, FGF2) creating feedback loops and downstream ubiquitination and proliferation signals.","evidence":"ChIP, promoter reporters, knockdown rescue, ubiquitination, and cytokine proliferation assays in myeloid cells","pmids":["21454682","21471217","22493287"],"confidence":"High","gaps":["Network interconnection in primary human progenitors incompletely mapped","Hierarchy of these targets not fully ordered"]},{"year":2012,"claim":"Closed an autocrine amplification loop showing HOXA10-induced FGF2 activates β-catenin, which feeds back to activate HOXA10 and CDX4.","evidence":"ChIP for β-catenin at HOXA10/CDX4 promoters, FGF2 neutralization, and β-catenin knockdown","pmids":["23038246"],"confidence":"High","gaps":["Loop dynamics over differentiation time not quantified","In vivo relevance to leukemia not directly tested"]},{"year":2012,"claim":"Added FKBP4/FKBP52 as a HOXA10-regulated decidualization gene.","evidence":"Reciprocal overexpression/knockdown with qRT-PCR and Western blot in human endometrial stromal cells","pmids":["22279148"],"confidence":"Medium","gaps":["Direct binding not shown","Single-lab data"]},{"year":2013,"claim":"Identified acetylation as a second post-translational control by showing PCAF acetylates HOXA10 at K338/K339 to impair ITGB3 activation and embryo adhesion.","evidence":"Co-IP, site-specific acetylation mapping, ChIP, reporter, and BeWo spheroid attachment assays","pmids":["24037888"],"confidence":"High","gaps":["Deacetylase reversing this mark not identified","Crosstalk with phosphorylation control not tested"]},{"year":2014,"claim":"Showed HOXA10 promotes carcinoma invasion through direct ZIC2 activation and through TGFβ2/p38 MAPK/MMP-3 signaling, expanding its pro-invasive transcriptional outputs.","evidence":"ChIP, truncated promoter reporters, knockdown/overexpression, TGFβ2 neutralization, and p38 inhibition in carcinoma cells","pmids":["28338202","24464212"],"confidence":"Medium","gaps":["Context dependence across tumor types not reconciled","Single-lab per pathway"]},{"year":2015,"claim":"Established HOXA10 as the terminator of emergency granulopoiesis through ARIH2/Triad1 activation, with HoxA9 antagonism set by differential tyrosine phosphorylation.","evidence":"HOXA10 and ARIH2 knockout mice, Triad1 re-expression rescue, reporter assays, and phosphorylation analysis","pmids":["25895533"],"confidence":"High","gaps":["Signals setting stage-specific phosphorylation states not defined","Human relevance not directly tested"]},{"year":2017,"claim":"Showed that programmed downregulation of HOXA10 in decidua is itself functional, enabling LIF/IL-6/STAT3-driven trophoblast invasion.","evidence":"HOXA10 siRNA in decidual cells, conditioned-medium invasion, STAT3 knockdown rescue, and cytokine ELISA","pmids":["28520923"],"confidence":"High","gaps":["Direct HOXA10 targets controlling LIF/IL-6 not identified","Temporal regulation of HOXA10 downregulation not mapped"]},{"year":2019,"claim":"Connected HOXA10 to apoptosis and epigenetic control in cancer through direct activation of BCL2 and of HDAC1, the latter increasing p53 acetylation when lost.","evidence":"ChIP, luciferase, p53 acetylation analysis, rescue experiments, and xenografts in gastric and hepatocellular carcinoma cells","pmids":["31364281","31440094"],"confidence":"Medium","gaps":["BCL2 finding from single lab","Tumor-type generality of HDAC1 axis not established"]},{"year":2020,"claim":"Identified MEIS1 as a physical HOXA10 cofactor in endometrium directing transcription of KAT2B and ETA required for decidualization.","evidence":"Co-IP, ChIP, reporter assays, CRISPR MEIS1 knockout, and functional rescue in endometrial stromal cells","pmids":["32197234"],"confidence":"High","gaps":["Genome-wide MEIS1-HOXA10 target set not defined","Stoichiometry of the complex unknown"]},{"year":2020,"claim":"Showed HOXA10 inhibits osteogenic differentiation of periodontal ligament stem cells via DKK1-mediated Wnt/β-catenin suppression, revealing context-dependent skeletal regulation opposite to its osteoblast role.","evidence":"Overexpression/knockdown, ALP/Alizarin staining, and LiCl/ICG-001 pharmacological rescue in hPDLSCs","pmids":["32299243"],"confidence":"Medium","gaps":["Reconciliation with HOXA10's osteoblast-activating role unresolved","Direct DKK1 binding not shown"]},{"year":2021,"claim":"Established HOXA10 as a positional-memory gene required for genomic stability and mitotic fidelity in somite-derived muscle stem cells.","evidence":"Satellite cell-specific conditional Hoxa10 knockout, regeneration assays, DNA methylation, and mitotic marker immunofluorescence","pmids":["34108202"],"confidence":"High","gaps":["Molecular targets mediating genomic stability not identified","Transcription-independent functions not excluded"]},{"year":2021,"claim":"Linked HOXA10 to m6A epitranscriptomic signaling in cancer through an ALKBH5/JAK2-m6A/STAT3 loop driving cisplatin resistance and a TGFB2/Smad/METTL3 axis driving EMT.","evidence":"MeRIP-seq, ChIP, RIP, CoIP, m6A assays, and in vivo rescue in ovarian and gastric cancer cells","pmids":["34496932","33563300"],"confidence":"High","gaps":["Direct versus indirect m6A regulation incompletely separated","Applicability across other cancers not tested"]},{"year":2021,"claim":"Defined a HOXA10/HDAC1/DNMT1/KLF4 axis in which HOXA10 promotes HDAC1 to stabilize DNMT1 and silence KLF4, driving lung adenocarcinoma progression.","evidence":"ChIP, CoIP, luciferase, methylation analysis, and xenograft rescue in lung adenocarcinoma cells","pmids":["33596966"],"confidence":"High","gaps":["Single tumor model","Endogenous requirement in patient tumors not directly tested"]},{"year":2022,"claim":"Demonstrated direct HOXA10 activation of E-cadherin via a defined promoter motif to enhance endometrial receptivity, and identified upstream NEAT1/CTCF repression of HOXA10.","evidence":"ChIP, promoter motif mutagenesis, reporter, spheroid attachment, in vivo mouse siRNA, RIP, and histone modification analysis","pmids":["35044439","35574918"],"confidence":"High","gaps":["Integration of NEAT1/CTCF with hormonal regulation unresolved","Quantitative balance of HOXA10 activation versus repression at implantation not modeled"]},{"year":null,"claim":"How HOXA10's post-translational code (phosphorylation, acetylation) and cofactor context (Pbx1, MEIS1) are integrated to specify tissue-specific activator versus repressor programs across hematopoiesis, endometrium, bone, and cancer remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No genome-wide occupancy map integrated across tissues","No structural model of cofactor-modulated DNA binding","Rules governing context-dependent activation versus repression undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,3,7,13,15,16,17,22,25,27,28,32]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[2,13,22,28,32,33]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[19]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[19,25]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,7,13,15,16,17,22,25,28,32]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,7,22,26]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,1,8,19,24,25,32]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,3,4,5,23]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,11,27,28,30,31]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[3,7,12,30,31]}],"complexes":[],"partners":["MEIS1","PBX1","SHP1","SHP2","HDAC2","PCAF","ALKBH5","CDX4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P31260","full_name":"Homeobox protein Hox-A10","aliases":["Homeobox protein Hox-1.8","Homeobox protein Hox-1H","PL"],"length_aa":410,"mass_kda":42.4,"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. Binds to the DNA sequence 5'-AA[AT]TTTTATTAC-3'","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P31260/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HOXA10","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"IPO7","stoichiometry":0.2},{"gene":"RANBP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/HOXA10","total_profiled":1310},"omim":[{"mim_id":"614060","title":"HOXA DISTAL TRANSCRIPT ANTISENSE RNA; HOTTIP","url":"https://www.omim.org/entry/614060"},{"mim_id":"613842","title":"GDNF-INDUCIBLE ZINC FINGER PROTEIN 1; GZF1","url":"https://www.omim.org/entry/613842"},{"mim_id":"613733","title":"MENIN 1; MEN1","url":"https://www.omim.org/entry/613733"},{"mim_id":"609880","title":"LYSINE ACETYLTRANSFERASE 7; KAT7","url":"https://www.omim.org/entry/609880"},{"mim_id":"601739","title":"MEIS HOMEOBOX 1; MEIS1","url":"https://www.omim.org/entry/601739"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"cervix","ntpm":44.8},{"tissue":"endometrium 1","ntpm":66.9},{"tissue":"skeletal muscle","ntpm":60.5}],"url":"https://www.proteinatlas.org/search/HOXA10"},"hgnc":{"alias_symbol":[],"prev_symbol":["HOX1H","HOX1"]},"alphafold":{"accession":"P31260","domains":[{"cath_id":"1.10.10.60","chopping":"345-409","consensus_level":"high","plddt":95.2362,"start":345,"end":409}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P31260","model_url":"https://alphafold.ebi.ac.uk/files/AF-P31260-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P31260-F1-predicted_aligned_error_v6.png","plddt_mean":59.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HOXA10","jax_strain_url":"https://www.jax.org/strain/search?query=HOXA10"},"sequence":{"accession":"P31260","fasta_url":"https://rest.uniprot.org/uniprotkb/P31260.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P31260/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P31260"}},"corpus_meta":[{"pmid":"7700356","id":"PMC_7700356","title":"Sexually dimorphic sterility 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role for Hoxa10 in male and female fertility.\",\n      \"method\": \"Targeted gene knockout in mice, phenotypic analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function mouse model with specific phenotypic readouts, foundational study replicated across the field\",\n      \"pmids\": [\"7700356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Maternal Hoxa10 expression in the uterus is required for embryo implantation; antisense oligonucleotide suppression of Hoxa10 before implantation significantly decreased implantation sites, while constitutive Hoxa10 expression increased litter size.\",\n      \"method\": \"In vivo uterine liposome-mediated gene transfection with antisense oligonucleotides or expression plasmid in pregnant mice; implantation site counting\",\n      \"journal\": \"Gene therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct gain- and loss-of-function in vivo with quantitative implantation readout, replicated concept across multiple papers\",\n      \"pmids\": [\"10981664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"HOXA10 protein interacts with and is repressed by SHP1 protein-tyrosine phosphatase in undifferentiated myeloid cells; SHP1 dephosphorylates tyrosine residues in the conserved HOXA10 homeodomain, increasing HoxA10 DNA binding affinity and transcriptional repression of target genes CYBB (gp91PHOX) and NCF2 (p67PHOX).\",\n      \"method\": \"Co-immunoprecipitation of SHP1 with HoxA10; phosphotyrosine analysis; transcriptional reporter assays; EMSA; tyrosine phosphorylation mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (Co-IP, mutagenesis, in vitro binding, reporter assays) in a single focused study\",\n      \"pmids\": [\"12145285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"HoxA10 represses transcription of CYBB (gp91PHOX) and NCF2 (p67PHOX) in undifferentiated myeloid cells through a Pbx1-independent repression domain (amino acids 224–249) that recruits histone deacetylase 2 (HDAC2); HDAC inhibitors abrogate this repression.\",\n      \"method\": \"Domain deletion/mutagenesis; co-immunoprecipitation of HOXA10 with HDAC2; HDAC inhibitor treatment; transcriptional reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis identified repression domain, Co-IP confirmed HDAC2 interaction, functional inhibitor experiments, multiple orthogonal methods\",\n      \"pmids\": [\"14512427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"HoxA10 represses NCF2 (p67PHOX) transcription via a homologous cis-element in the NCF2 promoter in a tyrosine phosphorylation- and histone deacetylase-dependent manner, paralleling its repression of CYBB; IFN-γ-induced tyrosine phosphorylation of the HoxA10 homeodomain decreases binding to this element and abrogates repression.\",\n      \"method\": \"Reporter assays with NCF2 promoter constructs; EMSA; IFN-γ treatment; HDAC inhibitor experiments; tyrosine phosphorylation analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal biochemical methods, mechanistic mutagenesis, replicated parallel mechanism from prior CYBB study\",\n      \"pmids\": [\"16210632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SHP2 protein-tyrosine phosphatase dephosphorylates HoxA10 in undifferentiated myeloid cells, maintaining HoxA10 in a DNA-binding-competent state that represses CYBB and NCF2 transcription; constitutively active SHP2 mutants (found in human AML) sustain HoxA10 dephosphorylation throughout myelopoiesis, persistently repressing myeloid differentiation genes.\",\n      \"method\": \"Co-immunoprecipitation of SHP2 with HoxA10; phosphotyrosine Western blot; transcriptional reporter assays; expression of constitutively active SHP2 mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, phosphorylation analysis, reporter assays, disease-relevant mutant validation in single focused study\",\n      \"pmids\": [\"17138561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Bisphenol A (BPA) drives HOXA10 expression through the HOXA10 estrogen response element (ERE) and indirectly through an autoregulatory element (ARE); BPA-induced HOXA10 upregulation via ERE is blocked by ER antagonist ICI, while ARE induction requires ER signaling and HOXA10 itself; in utero BPA exposure imprints lasting stromal HOXA10 overexpression uncoupled from estrogen stimulation in adult mice.\",\n      \"method\": \"Luciferase reporter assays with HOXA10-ERE and ARE constructs; ER antagonist ICI treatment; in vivo in utero BPA exposure; RT-PCR in 2- and 6-week-old offspring\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays with defined elements plus in vivo imprinting experiment, single lab\",\n      \"pmids\": [\"17093138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HOXA10 activates the Runx2 P1 promoter via a functional Hox core motif to induce osteoblast differentiation; HOXA10 also directly activates alkaline phosphatase, osteocalcin, and bone sialoprotein gene promoters; HOXA10 mediates chromatin hyperacetylation and H3K4 trimethylation at these loci; HOXA10 can induce osteoblast genes in Runx2-null cells, establishing a direct Runx2-independent pathway.\",\n      \"method\": \"ChIP; promoter reporter assays; siRNA knockdown; exogenous expression; analysis in Runx2-null cells; histone modification analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (ChIP, reporter assays, KD/OE, Runx2-null rescue), single rigorous study\",\n      \"pmids\": [\"17325044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HOXA10 negatively regulates IGFBP1 mRNA expression in decidualizing human endometrial stromal cells (HSC); overexpression of HOXA10 in HSC decreased IGFBP1 mRNA, while HOXA10 silencing increased IGFBP1 mRNA even in the presence of decidualization stimuli.\",\n      \"method\": \"HOXA10 overexpression and siRNA knockdown in human endometrial stromal cells; RT-PCR for IGFBP1\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain- and loss-of-function with defined molecular readout, single lab\",\n      \"pmids\": [\"17350963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"HOXA10 expression in ER-negative BT20 breast cancer cells increases p53 protein expression and reduces invasiveness through Matrigel; estradiol and tamoxifen increase HOXA10 mRNA in ER-positive MCF-7 cells.\",\n      \"method\": \"Constitutive HOXA10 expression in BT20 cells; Matrigel invasion assay; Western blot for p53; RT-PCR/Northern blot for HOXA10\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, single method per readout, but direct gain-of-function with two orthogonal phenotypic readouts\",\n      \"pmids\": [\"15044858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"HOXA10 inhibits invasive behavior of endometrial carcinoma cells and tumor dissemination by inducing E-cadherin expression through downregulation of the E-cadherin repressor Snail, thereby suppressing epithelial-mesenchymal transition.\",\n      \"method\": \"Enforced HOXA10 expression in endometrial carcinoma cells; Matrigel invasion assay; nude mouse xenograft; Western blot/RT-PCR for Snail and E-cadherin\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function in vitro and in vivo, defined molecular pathway (Snail/E-cadherin), single lab\",\n      \"pmids\": [\"16424022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Constitutively active SHP2 cooperates with HoxA10 overexpression to accelerate AML progression in mice; HoxA10 activates transcription of DUSP4 (encoding anti-apoptotic Mkp2) in myeloid progenitors, and SHP2-mediated dephosphorylation of HoxA10 maintains DUSP4 activation and CYBB/NCF2 repression throughout myelopoiesis.\",\n      \"method\": \"Murine bone marrow transplantation with HoxA10 overexpression and constitutively active SHP2; reporter assays; ChIP; phosphorylation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo bone marrow model plus biochemical experiments, single lab\",\n      \"pmids\": [\"19022774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Pbx1 negatively regulates Hoxa10-mediated transcription at osteoblast gene promoters (osteocalcin, bone sialoprotein) by associating with histone deacetylases and maintaining H3K9 methylation; during differentiation, Pbx1 dissociates from these promoters allowing Hoxa10 to recruit CBP/p300, increase histone acetylation, and decrease H3K9 methylation to activate transcription.\",\n      \"method\": \"ChIP; shRNA knockdown of Pbx1; wild-type and mutated promoter reporter assays; histone modification analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP, promoter mutagenesis, shRNA KD, multiple histone modification readouts in one study\",\n      \"pmids\": [\"20439491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HOXA10 directly represses KLF9 expression specifically in endometrial epithelial cells (not stromal cells) by binding to the KLF9 promoter; EMSA confirmed direct HOXA10–KLF9 promoter binding; targeted mutation of the HOXA10-binding site abolished repression.\",\n      \"method\": \"Transient transfection of HOXA10; reporter assays with KLF9 promoter; EMSA; targeted promoter mutation; immunohistochemistry\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — EMSA + promoter mutagenesis + reporter assays + cell-type specificity demonstrated, single lab\",\n      \"pmids\": [\"20463357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"miR-135a and miR-135b directly suppress HOXA10 expression by binding the HOXA10 3' UTR in endometrial stromal cells (cell-type specific; absent in MCF-7 cells); transfection with miR-135a/b or their inhibitors reciprocally altered HOXA10 mRNA and protein; luciferase reporter confirmed binding site.\",\n      \"method\": \"miRNA transfection; luciferase reporter with HOXA10 3' UTR; qPCR; Western blot; endometrial biopsy qPCR\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase + reciprocal gain/loss of function, cell-type specificity control, single lab\",\n      \"pmids\": [\"21956427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HoxA10 activates transcription of ARIH2 (encoding the E3 ubiquitin ligase Triad1) via two distinct HoxA10-binding cis elements in the ARIH2 promoter in myeloid cells; HoxA10-overexpressing myeloid cells show a Triad1-dependent increase in protein ubiquitination.\",\n      \"method\": \"Reporter assays with ARIH2 promoter cis elements; ChIP; Western blot for ubiquitination; Triad1 knockdown rescue experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP, promoter reporter assays, knockdown rescue, ubiquitination functional assay, multiple orthogonal methods\",\n      \"pmids\": [\"21454682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HoxA10 activates CDX4 transcription via a cis element in the CDX4 promoter; Cdx4 in turn activates the HOXA10 promoter via a Cdx4-binding cis element, forming a positive feedback loop; CDX4 knockdown decreases cytokine hypersensitivity in HoxA10-overexpressing myeloid progenitors.\",\n      \"method\": \"Reporter assays with CDX4 and HOXA10 promoter cis elements; ChIP; knockdown experiments; cytokine proliferation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP, bidirectional promoter reporter assays, knockdown, functional cytokine assays in single focused study\",\n      \"pmids\": [\"21471217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HoxA10 activates Fgf2 transcription via two cis elements in the FGF2 proximal promoter in myeloid cells, increasing Fgf2 secretion; autocrine Fgf2 activates a PI3K-dependent increase in β-catenin, stimulating myeloid progenitor proliferation and cytokine hypersensitivity.\",\n      \"method\": \"Reporter assays with FGF2 promoter cis elements; ChIP; Fgf2 secretion ELISA; PI3K inhibitor treatment; β-catenin Western blot; proliferation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP, promoter reporter assays, secretion measurement, pharmacological inhibition, downstream signaling validation, multiple orthogonal methods\",\n      \"pmids\": [\"22493287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"β-Catenin directly activates HOXA10 and CDX4 transcription via novel cis elements in their promoters in myeloid progenitor cells; HoxA10-induced Fgf2 production activates β-catenin in an autocrine manner, which then further amplifies HOXA10 and CDX4 expression.\",\n      \"method\": \"Reporter assays; ChIP for β-catenin at HOXA10 and CDX4 promoters; Fgf2 neutralization; β-catenin knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP at defined cis elements, promoter reporter assays, signaling perturbation, multiple orthogonal methods\",\n      \"pmids\": [\"23038246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PCAF acetyltransferase physically interacts with HOXA10 and acetylates it at lysines K338 and K339, impairing HOXA10-mediated transcription of ITGB3 (β3-integrin) and reducing embryo adhesiveness in endometrial epithelial cells.\",\n      \"method\": \"Co-immunoprecipitation; confocal immunofluorescence; luciferase reporter; ChIP; Western blot; BeWo spheroid attachment assay; siRNA knockdown/overexpression of PCAF\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — Co-IP, site-specific acetylation mapping (K338/K339), reporter assays, ChIP, functional adhesion assay, multiple orthogonal methods\",\n      \"pmids\": [\"24037888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HOXA10 regulates FKBP4 (FKBP52) expression in human endometrial stromal cells; overexpression of HOXA10 increased FKBP4 mRNA and protein, while HOXA10 knockdown decreased FKBP4 expression and impaired decidualization.\",\n      \"method\": \"HOXA10 overexpression and siRNA knockdown in HESCs; qRT-PCR; Western blot; decidualization markers (IGFBP1)\",\n      \"journal\": \"Reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss of function, single lab, two orthogonal methods\",\n      \"pmids\": [\"22279148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HOXA10 directly regulates Calpain5 expression in endometrial cells; transfection with HOXA10 expression construct increased Calpain5 mRNA, while HOXA10 siRNA decreased Calpain5 expression, suggesting HOXA10 promotes apoptosis resistance via a Calpain5/caspase pathway.\",\n      \"method\": \"HOXA10 overexpression and siRNA in HESC cells; qRT-PCR; immunohistochemistry\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — reciprocal gain/loss of function, single lab, single readout method\",\n      \"pmids\": [\"18829447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HOXA10 controls hematopoietic stem cell self-renewal and repopulating capacity in a dose-dependent manner; intermediate HOXA10 levels expand HSCs ~15-fold after in vitro culture, while high levels block erythroid and megakaryocyte development; downstream targets include HLF, Dkk-1, Gfi-1, and Gata-1, with HOXA10 binding sites confirmed in HLF, Dkk-1, and Gata-1, and transcriptional activation of Dkk-1 and Gfi-1 demonstrated.\",\n      \"method\": \"Doxycycline-inducible transgenic mice; bone marrow repopulation assays; gene expression profiling; HOXA10 binding site analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible in vivo model with dose-dependent phenotype, downstream gene activation confirmed, single rigorous study\",\n      \"pmids\": [\"17234739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HoxA10 terminates emergency granulopoiesis by activating ARIH2 (Triad1) transcription during myeloid differentiation; HOXA10-knockout mice exhibit overwhelming fatal emergency granulopoiesis reversed by re-expression of Triad1 in bone marrow; HoxA9 antagonizes this by repressing ARIH2 transcription; differentiation-stage-specific ARIH2 transcription is regulated by tyrosine phosphorylation states of HoxA9 and HoxA10.\",\n      \"method\": \"HOXA10 knockout mice; bone marrow Triad1 re-expression rescue; ARIH2 knockout mice; reporter assays; phosphorylation analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO with rescue, genetic epistasis between HoxA9 and HoxA10, multiple orthogonal methods\",\n      \"pmids\": [\"25895533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Downregulation of HOXA10 in decidual cells after embryo implantation promotes trophoblast invasion by increasing LIF and IL-6 secretion, which activates STAT3 (Tyr705) in trophoblast cells, upregulating MMP activity and decreasing TIMPs; STAT3 knockdown in trophoblasts rescues the invasion mediated by HOXA10-depleted decidual cells.\",\n      \"method\": \"HOXA10 siRNA depletion of decidual cells; conditioned medium trophoblast invasion assay; MMP activity assay; STAT3 knockdown; Western blot for phospho-STAT3; ELISA for LIF and IL-6\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (conditioned medium assay, STAT3 rescue, MMP assay, cytokine ELISA), defined paracrine pathway\",\n      \"pmids\": [\"28520923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MEIS1 physically interacts with HOXA10 in human endometrial stromal cells; the MEIS1-HOXA10 complex binds the promoters of KAT2B and ETA and regulates their transcriptional activity; MEIS1 deficiency (siRNA and CRISPR-Cas9) impairs decidualization, and KAT2B/ETA overexpression partially rescues decidualization defects in MEIS1-knockout cells.\",\n      \"method\": \"Co-immunoprecipitation of MEIS1 with HOXA10; siRNA and CRISPR-Cas9 MEIS1 knockout; luciferase reporter; ChIP for MEIS1-HOXA10 at KAT2B and ETA promoters; rescue overexpression\",\n      \"journal\": \"Journal of molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — Co-IP, ChIP, promoter reporter, CRISPR KO, functional rescue, multiple orthogonal methods in single study\",\n      \"pmids\": [\"32197234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Hoxa10 is required for genomic stability and mitotic function in somite-derived satellite cells; satellite cell-specific Hoxa10 ablation in mice causes genomic instability, mitotic catastrophe, and impaired regeneration specifically of somite-derived muscles (not cranial mesoderm-derived muscles), establishing Hoxa10 as a positional memory gene in adult muscle stem cells.\",\n      \"method\": \"Satellite cell-specific conditional Hoxa10 knockout mice; muscle regeneration assays; DNA methylation analysis of Hox-A locus; immunofluorescence for mitotic markers\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with tissue-specific phenotype and molecular mechanism (genomic instability, mitotic catastrophe), lineage-specific control\",\n      \"pmids\": [\"34108202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HOXA10 acts as an upstream transcription factor for ALKBH5 and forms a regulatory loop with it; the ALKBH5-HOXA10 loop activates the JAK2/STAT3 signaling pathway by mediating ALKBH5-dependent m6A demethylation of JAK2 mRNA, promoting cisplatin resistance in epithelial ovarian cancer cells.\",\n      \"method\": \"MeRIP-seq; RNA-seq; ChIP; RNA immunoprecipitation; luciferase reporter; in vitro and in vivo functional assays; ALKBH5/HOXA10 knockdown\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — MeRIP-seq for m6A mapping, ChIP for HOXA10 at ALKBH5 promoter, RIP, reporter assay, in vivo rescue, multiple orthogonal methods\",\n      \"pmids\": [\"34496932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HOXA10 promotes gastric cancer EMT and metastasis by binding the TGFB2 promoter, activating TGFB2 transcription and secretion, triggering TGFβ/Smad signaling with Smad2/3 nuclear translocation; the downstream Smad proteins mediate METTL3 expression (confirmed by CoIP and ChIP), and METTL3 elevates overall m6A levels to drive EMT.\",\n      \"method\": \"ChIP-qPCR for HOXA10 at TGFB2 promoter; dual-luciferase reporter; CoIP of Smad proteins with METTL3; colorimetric m6A assay; in vivo lung metastasis models; rescue experiments\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP, CoIP, reporter assay, m6A assay, in vivo rescue, multiple orthogonal methods\",\n      \"pmids\": [\"33563300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HOXA10 binds the BCL2 promoter region and induces BCL2 expression, thereby inhibiting the intrinsic apoptosis pathway and promoting gastric cancer cell proliferation.\",\n      \"method\": \"ChIP-qPCR for HOXA10 at BCL2 promoter; qRT-PCR; Western blot; rescue experiments; in vivo xenograft\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR with rescue experiment, single lab\",\n      \"pmids\": [\"31364281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HOXA10 knockdown in hepatocellular carcinoma cells suppresses HDAC1 transcription (via direct HOXA10 binding to HDAC1 promoter confirmed by ChIP and luciferase assay), leading to increased p53 acetylation at Lys382, cell cycle arrest, and apoptosis; HDAC1 overexpression reverses the effects of HOXA10 knockdown.\",\n      \"method\": \"siRNA knockdown; ChIP and luciferase reporter for HOXA10 at HDAC1 promoter; flow cytometry; Western blot for p53 acetylation; in vivo xenograft; rescue experiments\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP, promoter reporter, p53 acetylation site-specific analysis, rescue experiments, multiple orthogonal methods\",\n      \"pmids\": [\"31440094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HOXA10 promotes HDAC1 expression in lung adenocarcinoma; HDAC1 deacetylates DNMT1 to stabilize it, and DNMT1 methylates the KLF4 promoter to silence KLF4, creating a HOXA10/HDAC1/DNMT1/KLF4 axis that drives LAD proliferation and migration; CoIP confirmed HDAC1-DNMT1 interaction.\",\n      \"method\": \"ChIP; dual luciferase assay; CoIP of HDAC1 with DNMT1; siRNA/shRNA depletion; Western blot; in vivo xenograft\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP, CoIP, luciferase, methylation analysis, in vivo rescue, multiple orthogonal methods in single study\",\n      \"pmids\": [\"33596966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HOXA10 directly binds a conserved motif (TGTACTAAAAA) in the E-cadherin promoter to activate E-cadherin expression, improving endometrial receptivity and embryo adhesion; siRNA knockdown of HOXA10 in mice reduced implantation and live birth rates.\",\n      \"method\": \"ChIP for HOXA10 at E-cadherin promoter; dual luciferase reporter; siRNA and overexpression transfection; JEG-3 spheroid attachment assay; in vivo HOXA10 siRNA mouse model\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP, promoter motif mutagenesis, reporter assay, in vitro adhesion assay, and in vivo mouse model in a single study\",\n      \"pmids\": [\"35044439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HOXA10 directly binds the ZIC2 promoter and upregulates ZIC2 transcription in nasopharyngeal carcinoma cells; luciferase reporters with truncated ZIC2 promoter sequences confirmed the HOXA10 binding site; ZIC2 knockdown reverses HOXA10-induced proliferation and invasion.\",\n      \"method\": \"ChIP; luciferase reporters with truncated ZIC2 promoter; HOXA10 overexpression; ZIC2 siRNA rescue\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and promoter reporter assays with truncation mapping, rescue experiment, single lab\",\n      \"pmids\": [\"28338202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HOXA10 promotes pancreatic cancer cell invasion and MMP-3 expression via TGFβ2-mediated activation of the p38 MAPK pathway; HOXA10 knockdown decreases TGFβ2 and MMP-3 expression and suppresses p38 activation; TGFβ2 neutralization or p38 inhibition blocks HOXA10-mediated invasion.\",\n      \"method\": \"siRNA knockdown; overexpression; TGFβ2 neutralizing antibody; p38 inhibitor (SB239063); invasion assays; Western blot\",\n      \"journal\": \"Digestive diseases and sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and antibody interventions plus reciprocal KD/OE, defined pathway, single lab\",\n      \"pmids\": [\"24464212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CTCF binds a 20 bp motif in the HOXA10 core promoter region and negatively regulates HOXA10 expression in breast cancer cells by maintaining H3K27me3 inactivation marks at the HOXA10 promoter; in silico and in vitro mutation assays confirmed the CTCF binding site.\",\n      \"method\": \"ChIP for CTCF and H3K27me3 at HOXA10 promoter; promoter reporter assay; in silico binding site prediction; mutation assay; CTCF overexpression and knockdown\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, promoter reporter, site mutagenesis, histone modification analysis, single lab\",\n      \"pmids\": [\"26478432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HOXA10 inhibits osteogenic differentiation of periodontal ligament stem cells by increasing DKK1 expression and reducing nuclear β-catenin accumulation; HOXA10 overexpression reduces nuclear β-catenin and increases DKK1; effects are rescued by Wnt/β-catenin activator LiCl, and HOXA10 knockdown effects are antagonized by Wnt inhibitor ICG-001.\",\n      \"method\": \"HOXA10 overexpression and knockdown in hPDLSCs; ALP and Alizarin Red staining; Western blot for nuclear β-catenin and DKK1; LiCl and ICG-001 treatment\",\n      \"journal\": \"Connective tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological rescue with both activator and inhibitor, reciprocal gain/loss of function, multiple readouts, single lab\",\n      \"pmids\": [\"32299243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LncRNA NEAT1 binds CTCF and recruits it to the HOXA10 promoter; CTCF binding downregulates HOXA10 gene expression by regulating histone modification levels; the lncRNA NEAT1/CTCF/HOXA10 signaling pathway regulates endometrial epithelial cell proliferation and endometrial receptivity establishment.\",\n      \"method\": \"RNA immunoprecipitation; ChIP; histone modification analysis; in vitro and in vivo knockdown models; trophoblast attachment assay\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and ChIP confirm physical interactions, histone modification readout, functional rescue, single lab\",\n      \"pmids\": [\"35574918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"EZH2 (component of Polycomb Repressor Complex 2, PRC2) represses HOXA10 expression in T-cell lines; siRNA knockdown of EZH2 in JURKAT cells enhanced HOXA10 expression, and DZNep (EZH2/PRC2 inhibitor) treatment elevated HOXA10 expression; HOXA10 and HOXA9 directly activated ID2 expression (ChIP and promoter analysis).\",\n      \"method\": \"siRNA knockdown of EZH2; DZNep pharmacological inhibition; ChIP; promoter reporter; overexpression\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological EZH2 inhibition, ChIP, reporter assay, single lab\",\n      \"pmids\": [\"20565746\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HOXA10 is a homeodomain transcription factor that activates or represses target gene promoters through direct DNA binding; its activity is regulated by tyrosine phosphorylation (reducing DNA binding affinity, mediated by IFN-γ signaling and reversed by SHP1/SHP2 phosphatases), acetylation by PCAF (at K338/K339, impairing transcriptional activation), and by co-factor complexes (Pbx1 recruiting HDACs to repress, Meis1 enhancing activity); in myeloid cells HOXA10 represses phagocyte oxidase genes (CYBB, NCF2) via HDAC2 recruitment and activates FGF2, CDX4, ARIH2/Triad1, and DUSP4 to control progenitor expansion, differentiation, and emergency granulopoiesis; in endometrium HOXA10 directly activates ITGB3 and E-cadherin promoters and represses KLF9 and IGFBP1, regulating implantation and decidualization via co-factors including MEIS1; in bone, HOXA10 activates Runx2, alkaline phosphatase, osteocalcin, and bone sialoprotein through chromatin hyperacetylation and H3K4 trimethylation; in various cancers HOXA10 drives EMT via TGFB2/Smad/METTL3 signaling, activates BCL2 and HDAC1 (the latter suppressing KLF4 via DNMT1-mediated methylation), and acts upstream of the ALKBH5/JAK2(m6A)/STAT3 cisplatin-resistance axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HOXA10 is a homeodomain transcription factor that establishes positional identity and orchestrates lineage-specific differentiation programs, with foundational genetic evidence linking it to skeletal patterning, male and female fertility, and embryo implantation [#0, #1]. It acts as a sequence-specific DNA-binding regulator that can either activate or repress target promoters depending on cofactor context and post-translational state. Its DNA-binding activity is controlled by tyrosine phosphorylation of the homeodomain: the phosphatases SHP1 and SHP2 dephosphorylate HOXA10 to sustain a DNA-binding-competent repressor state, while IFN-\\u03b3-induced phosphorylation lowers affinity and relieves repression [#2, #5, #4]. PCAF acetylates HOXA10 at K338/K339 to impair its transcriptional activation of targets such as ITGB3 [#19]. In myeloid progenitors, HOXA10 represses the phagocyte oxidase genes CYBB and NCF2 by recruiting HDAC2 through a Pbx1-independent repression domain, while activating FGF2, CDX4, ARIH2/Triad1, and DUSP4 to drive progenitor expansion, autocrine FGF2/PI3K/\\u03b2-catenin signaling, and the timely termination of emergency granulopoiesis [#3, #15, #16, #17, #18, #23], and it governs hematopoietic stem cell self-renewal in a dose-dependent manner [#22]. In endometrium, HOXA10 directly activates ITGB3 and E-cadherin and represses KLF9 and IGFBP1, working with the cofactor MEIS1 to regulate receptivity, implantation, and decidualization [#13, #19, #32, #25, #8]. In osteoblast differentiation it activates Runx2, alkaline phosphatase, osteocalcin, and bone sialoprotein through chromatin hyperacetylation and H3K4 trimethylation, with Pbx1 switching the locus between HDAC-mediated repression and CBP/p300-mediated activation [#7, #12]. In cancers, HOXA10 promotes EMT, proliferation, and chemoresistance by activating TGFB2/Smad/METTL3 m6A signaling, BCL2, HDAC1 (suppressing KLF4 via DNMT1 methylation), and an ALKBH5/JAK2-m6A/STAT3 cisplatin-resistance loop [#28, #29, #31, #27]. HOXA10 is itself controlled by upstream repression via EZH2/PRC2 and CTCF-dependent histone modification and by miR-135a/b targeting its 3' UTR [#38, #35, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established that HOXA10 is required in vivo for axial patterning and reproductive function, defining the biological problem space the protein operates in.\",\n      \"evidence\": \"Targeted Hoxa10 knockout in mice with phenotypic analysis\",\n      \"pmids\": [\"7700356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify direct transcriptional targets\", \"Tissue-autonomous versus systemic contributions not separated\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated that maternal uterine HOXA10 is functionally required for embryo implantation, converting the knockout phenotype into a manipulable dose-dependent process.\",\n      \"evidence\": \"In vivo uterine antisense and expression-plasmid transfection with implantation site counting in mice\",\n      \"pmids\": [\"10981664\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream implantation effectors not defined\", \"Direct DNA targets not identified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the first post-translational control of HOXA10, showing tyrosine phosphorylation of the homeodomain governs DNA binding and that SHP1 dephosphorylation enables repression of myeloid oxidase genes.\",\n      \"evidence\": \"Co-IP, phosphotyrosine mapping, EMSA, and reporter assays in myeloid cells\",\n      \"pmids\": [\"12145285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for phosphorylation not identified here\", \"In vivo relevance to myelopoiesis not yet established\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified the mechanism of HOXA10 repression at oxidase genes as recruitment of HDAC2 via a discrete Pbx1-independent repression domain, mechanistically distinguishing repression from cofactor-dependent activity.\",\n      \"evidence\": \"Domain mutagenesis, HDAC2 Co-IP, and HDAC inhibitor reporter assays in myeloid cells\",\n      \"pmids\": [\"14512427\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other corepressors at these loci not mapped\", \"Structural basis of the repression domain unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Generalized the phosphorylation-dependent repression model by showing IFN-\\u03b3 signaling relieves HOXA10 repression of NCF2, linking cytokine signaling to oxidase gene derepression during differentiation.\",\n      \"evidence\": \"NCF2 promoter reporters, EMSA, IFN-\\u03b3 treatment, and HDAC inhibitor experiments\",\n      \"pmids\": [\"16210632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of IFN-\\u03b3-activated tyrosine kinase not defined\", \"Quantitative contribution to differentiation timing unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Completed the phosphatase regulatory axis and connected it to disease by showing SHP2 sustains HOXA10 dephosphorylation, with leukemia-associated activating SHP2 mutants persistently repressing differentiation genes.\",\n      \"evidence\": \"Co-IP, phosphorylation analysis, reporter assays, and constitutively active SHP2 mutants in myeloid cells\",\n      \"pmids\": [\"17138561\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct causation in human AML not tested here\", \"Full target set sustained by SHP2 not enumerated\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed HOXA10 expression is hormonally and environmentally regulated through estrogen-response and autoregulatory promoter elements, identifying HOXA10 as a node for endocrine disruptor imprinting.\",\n      \"evidence\": \"ERE/ARE reporter assays, ER antagonist treatment, and in utero BPA exposure in mice\",\n      \"pmids\": [\"17093138\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab reporter and imprinting data\", \"Mechanism of persistent estrogen-uncoupled expression not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Established HOXA10 as a direct activator of the osteoblast differentiation program acting upstream of and parallel to Runx2 through chromatin modification.\",\n      \"evidence\": \"ChIP, promoter reporters, siRNA, Runx2-null rescue, and histone modification analysis\",\n      \"pmids\": [\"17325044\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Histone-modifying enzymes recruited not yet identified\", \"Endogenous requirement in bone in vivo not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended HOXA10 transcriptional control into endometrial decidualization by showing it negatively regulates IGFBP1.\",\n      \"evidence\": \"Reciprocal HOXA10 overexpression/knockdown with RT-PCR in human endometrial stromal cells\",\n      \"pmids\": [\"17350963\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter binding to IGFBP1 not shown\", \"Cofactor dependence not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked the phosphatase/HOXA10 axis to leukemogenesis and added DUSP4 as an anti-apoptotic activated target sustaining myeloid progenitor survival.\",\n      \"evidence\": \"Murine bone marrow transplantation with HoxA10 and active SHP2, ChIP, and reporter assays\",\n      \"pmids\": [\"19022774\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab in vivo model\", \"Relative contribution of DUSP4 versus oxidase repression to AML not dissected\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified Calpain5 as a HOXA10-regulated gene implicating HOXA10 in endometrial apoptosis resistance.\",\n      \"evidence\": \"HOXA10 overexpression/siRNA with qRT-PCR and IHC in endometrial cells\",\n      \"pmids\": [\"18829447\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single readout method\", \"Direct binding to Calpain5 promoter not demonstrated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved the molecular switch by which Pbx1 converts HOXA10 from repressor to activator at bone gene promoters via differential corepressor/coactivator recruitment.\",\n      \"evidence\": \"ChIP, Pbx1 shRNA, promoter mutagenesis, and histone modification analysis\",\n      \"pmids\": [\"20439491\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal triggering Pbx1 dissociation not identified\", \"Generality of switch to non-bone loci untested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated direct, cell-type-specific repression of KLF9 by HOXA10 binding the KLF9 promoter, refining endometrial epithelial versus stromal target logic.\",\n      \"evidence\": \"Reporter assays, EMSA, and promoter-site mutation in endometrial cells\",\n      \"pmids\": [\"20463357\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Basis of epithelial-specific activity not defined\", \"In vivo consequence of KLF9 derepression not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established HOXA10 as a dose-dependent regulator of hematopoietic stem cell self-renewal with defined downstream targets.\",\n      \"evidence\": \"Doxycycline-inducible transgenic mice, repopulation assays, expression profiling, and binding-site analysis (HLF, Dkk-1, Gata-1)\",\n      \"pmids\": [\"17234739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of dose-dependent lineage block unclear\", \"Direct versus indirect targets incompletely separated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placed HOXA10 within Polycomb-controlled gene regulation, showing EZH2/PRC2 represses HOXA10 and that HOXA10 activates ID2 in lymphoid cells.\",\n      \"evidence\": \"EZH2 siRNA, DZNep inhibition, ChIP, and reporter assays in T-cell lines\",\n      \"pmids\": [\"20565746\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lineage context\", \"Functional consequence of EZH2-mediated HOXA10 repression not assayed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined a HOXA10-driven myeloid transcriptional network (ARIH2/Triad1, CDX4, FGF2) creating feedback loops and downstream ubiquitination and proliferation signals.\",\n      \"evidence\": \"ChIP, promoter reporters, knockdown rescue, ubiquitination, and cytokine proliferation assays in myeloid cells\",\n      \"pmids\": [\"21454682\", \"21471217\", \"22493287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Network interconnection in primary human progenitors incompletely mapped\", \"Hierarchy of these targets not fully ordered\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Closed an autocrine amplification loop showing HOXA10-induced FGF2 activates \\u03b2-catenin, which feeds back to activate HOXA10 and CDX4.\",\n      \"evidence\": \"ChIP for \\u03b2-catenin at HOXA10/CDX4 promoters, FGF2 neutralization, and \\u03b2-catenin knockdown\",\n      \"pmids\": [\"23038246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Loop dynamics over differentiation time not quantified\", \"In vivo relevance to leukemia not directly tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Added FKBP4/FKBP52 as a HOXA10-regulated decidualization gene.\",\n      \"evidence\": \"Reciprocal overexpression/knockdown with qRT-PCR and Western blot in human endometrial stromal cells\",\n      \"pmids\": [\"22279148\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding not shown\", \"Single-lab data\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified acetylation as a second post-translational control by showing PCAF acetylates HOXA10 at K338/K339 to impair ITGB3 activation and embryo adhesion.\",\n      \"evidence\": \"Co-IP, site-specific acetylation mapping, ChIP, reporter, and BeWo spheroid attachment assays\",\n      \"pmids\": [\"24037888\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Deacetylase reversing this mark not identified\", \"Crosstalk with phosphorylation control not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed HOXA10 promotes carcinoma invasion through direct ZIC2 activation and through TGF\\u03b22/p38 MAPK/MMP-3 signaling, expanding its pro-invasive transcriptional outputs.\",\n      \"evidence\": \"ChIP, truncated promoter reporters, knockdown/overexpression, TGF\\u03b22 neutralization, and p38 inhibition in carcinoma cells\",\n      \"pmids\": [\"28338202\", \"24464212\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context dependence across tumor types not reconciled\", \"Single-lab per pathway\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established HOXA10 as the terminator of emergency granulopoiesis through ARIH2/Triad1 activation, with HoxA9 antagonism set by differential tyrosine phosphorylation.\",\n      \"evidence\": \"HOXA10 and ARIH2 knockout mice, Triad1 re-expression rescue, reporter assays, and phosphorylation analysis\",\n      \"pmids\": [\"25895533\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals setting stage-specific phosphorylation states not defined\", \"Human relevance not directly tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed that programmed downregulation of HOXA10 in decidua is itself functional, enabling LIF/IL-6/STAT3-driven trophoblast invasion.\",\n      \"evidence\": \"HOXA10 siRNA in decidual cells, conditioned-medium invasion, STAT3 knockdown rescue, and cytokine ELISA\",\n      \"pmids\": [\"28520923\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct HOXA10 targets controlling LIF/IL-6 not identified\", \"Temporal regulation of HOXA10 downregulation not mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected HOXA10 to apoptosis and epigenetic control in cancer through direct activation of BCL2 and of HDAC1, the latter increasing p53 acetylation when lost.\",\n      \"evidence\": \"ChIP, luciferase, p53 acetylation analysis, rescue experiments, and xenografts in gastric and hepatocellular carcinoma cells\",\n      \"pmids\": [\"31364281\", \"31440094\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"BCL2 finding from single lab\", \"Tumor-type generality of HDAC1 axis not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified MEIS1 as a physical HOXA10 cofactor in endometrium directing transcription of KAT2B and ETA required for decidualization.\",\n      \"evidence\": \"Co-IP, ChIP, reporter assays, CRISPR MEIS1 knockout, and functional rescue in endometrial stromal cells\",\n      \"pmids\": [\"32197234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide MEIS1-HOXA10 target set not defined\", \"Stoichiometry of the complex unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed HOXA10 inhibits osteogenic differentiation of periodontal ligament stem cells via DKK1-mediated Wnt/\\u03b2-catenin suppression, revealing context-dependent skeletal regulation opposite to its osteoblast role.\",\n      \"evidence\": \"Overexpression/knockdown, ALP/Alizarin staining, and LiCl/ICG-001 pharmacological rescue in hPDLSCs\",\n      \"pmids\": [\"32299243\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation with HOXA10's osteoblast-activating role unresolved\", \"Direct DKK1 binding not shown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established HOXA10 as a positional-memory gene required for genomic stability and mitotic fidelity in somite-derived muscle stem cells.\",\n      \"evidence\": \"Satellite cell-specific conditional Hoxa10 knockout, regeneration assays, DNA methylation, and mitotic marker immunofluorescence\",\n      \"pmids\": [\"34108202\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular targets mediating genomic stability not identified\", \"Transcription-independent functions not excluded\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked HOXA10 to m6A epitranscriptomic signaling in cancer through an ALKBH5/JAK2-m6A/STAT3 loop driving cisplatin resistance and a TGFB2/Smad/METTL3 axis driving EMT.\",\n      \"evidence\": \"MeRIP-seq, ChIP, RIP, CoIP, m6A assays, and in vivo rescue in ovarian and gastric cancer cells\",\n      \"pmids\": [\"34496932\", \"33563300\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect m6A regulation incompletely separated\", \"Applicability across other cancers not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a HOXA10/HDAC1/DNMT1/KLF4 axis in which HOXA10 promotes HDAC1 to stabilize DNMT1 and silence KLF4, driving lung adenocarcinoma progression.\",\n      \"evidence\": \"ChIP, CoIP, luciferase, methylation analysis, and xenograft rescue in lung adenocarcinoma cells\",\n      \"pmids\": [\"33596966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single tumor model\", \"Endogenous requirement in patient tumors not directly tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated direct HOXA10 activation of E-cadherin via a defined promoter motif to enhance endometrial receptivity, and identified upstream NEAT1/CTCF repression of HOXA10.\",\n      \"evidence\": \"ChIP, promoter motif mutagenesis, reporter, spheroid attachment, in vivo mouse siRNA, RIP, and histone modification analysis\",\n      \"pmids\": [\"35044439\", \"35574918\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of NEAT1/CTCF with hormonal regulation unresolved\", \"Quantitative balance of HOXA10 activation versus repression at implantation not modeled\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HOXA10's post-translational code (phosphorylation, acetylation) and cofactor context (Pbx1, MEIS1) are integrated to specify tissue-specific activator versus repressor programs across hematopoiesis, endometrium, bone, and cancer remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No genome-wide occupancy map integrated across tissues\", \"No structural model of cofactor-modulated DNA binding\", \"Rules governing context-dependent activation versus repression undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 3, 7, 13, 15, 16, 17, 22, 25, 27, 28, 32]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [2, 13, 22, 28, 32, 33]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [19, 25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 7, 13, 15, 16, 17, 22, 25, 28, 32]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 7, 22, 26]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0, 1, 8, 19, 24, 25, 32]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3, 4, 5, 23]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 11, 27, 28, 30, 31]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [3, 7, 12, 30, 31]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MEIS1\", \"PBX1\", \"SHP1\", \"SHP2\", \"HDAC2\", \"PCAF\", \"ALKBH5\", \"CDX4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}