{"gene":"HOXA10","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1995,"finding":"Targeted homozygous mutation of Hoxa10 in mice causes anterior homeotic transformation of lumbar vertebrae, bilateral cryptorchidism with spermatogenesis defects in males, and ~80% sterility in females due to embryo death between days 2.5–3.5 post coitum, coinciding with maternal Hoxa10 expression in distal oviductal and uterine epithelium, establishing a role for Hoxa10 in male and female fertility.","method":"Targeted gene disruption (knockout mouse), histology, timed embryo analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 — foundational knockout study with multiple orthogonal phenotypic readouts; highly cited","pmids":["7700356"],"is_preprint":false},{"year":2000,"finding":"Maternal Hoxa10 expression in the uterus is essential for embryo implantation; antisense oligonucleotide knockdown of Hoxa10 in the uterus significantly reduced implantation sites, while constitutive Hoxa10 overexpression increased litter size.","method":"In vivo uterine transfection of DNA/liposome complexes with antisense or expression constructs in day-2 pregnant mice","journal":"Gene therapy","confidence":"High","confidence_rationale":"Tier 2 — direct in vivo gain- and loss-of-function with specific implantation phenotype","pmids":["10981664"],"is_preprint":false},{"year":2004,"finding":"In vivo uterine transfection of Hoxa10 in ovariectomized, estrogen-primed mice phenocopied progesterone treatment, inducing epithelial calcitonin and stromal prolactin expression, demonstrating that Hoxa10 mediates progesterone-induced functional differentiation of endometrial epithelium and stroma.","method":"In vivo uterine transfection, immunohistochemistry, gene expression analysis in ovariectomized mice","journal":"Molecular reproduction and development","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional experiment with defined cellular outcome; single lab","pmids":["14648870"],"is_preprint":false},{"year":2007,"finding":"HOXA10 activates the Runx2 P1 promoter via a Hox core motif element in response to BMP2, and directly activates osteoblastic phenotypic genes (alkaline phosphatase, osteocalcin, bone sialoprotein); HOXA10 promotes chromatin hyperacetylation and H3K4 trimethylation at these gene promoters and can induce osteoblast genes even in Runx2-null cells.","method":"Reporter assays, ChIP, siRNA knockdown, exogenous expression, Runx2-null cell complementation, chromatin remodeling assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including ChIP, mutagenesis of cis-elements, reconstitution in null cells","pmids":["17325044"],"is_preprint":false},{"year":2007,"finding":"HOXA10 negatively regulates IGFBP1 mRNA expression in human endometrial stromal cells during decidualization; overexpression of HOXA10 decreased IGFBP1 mRNA while siRNA knockdown increased it even in the presence of decidualizing stimuli.","method":"Overexpression and siRNA knockdown in human endometrial stromal cells (HSC), qRT-PCR","journal":"Molecular human reproduction","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal gain/loss-of-function in primary cells with defined transcriptional readout; single lab","pmids":["17350963"],"is_preprint":false},{"year":2007,"finding":"Controlled transgenic expression of HOXA10 in mice expanded hematopoietic stem cell (HSC) repopulating capacity ~15-fold after in vitro culture at intermediate levels, while high HOXA10 levels blocked erythroid and megakaryocyte development; HOXA10 binding sites were found in HLF, Dkk-1, and Gata-1, and HOXA10 transcriptionally activated Dkk-1 and Gfi-1.","method":"Doxycycline-inducible transgenic mouse model, bone marrow transplantation/repopulation assays, ChIP, transcriptional activation assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — dose-controlled transgenic system with multiple phenotypic readouts and direct promoter binding evidence","pmids":["17234739"],"is_preprint":false},{"year":2006,"finding":"Enforced HOXA10 expression in endometrial carcinoma cells inhibited invasive behavior in vitro and tumor dissemination in nude mice by inducing E-cadherin expression through down-regulation of Snail; HOXA10 promoter methylation correlated with reduced expression and higher tumor grade.","method":"Forced expression in carcinoma cell lines, nude mouse xenograft model, invasion assay, bisulfite sequencing","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — in vitro and in vivo functional experiments with defined mechanistic pathway (HOXA10→repression of Snail→E-cadherin induction)","pmids":["16424022"],"is_preprint":false},{"year":2005,"finding":"HoxA10 represses transcription of CYBB (gp91phox) and NCF2 (p67phox) in undifferentiated myeloid cells by binding homologous cis-elements in these promoters; repression requires histone deacetylase recruitment; phosphorylation of two tyrosine residues in the HoxA10 homeodomain by cytokine-activated pathways decreases DNA binding and abrogates repression during myeloid differentiation.","method":"Reporter assays, EMSA, ChIP, mutagenesis of homeodomain tyrosine residues, HDAC activity assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal biochemical methods including mutagenesis and HDAC recruitment; replicated across CYBB and NCF2","pmids":["16210632"],"is_preprint":false},{"year":2006,"finding":"SHP2 protein-tyrosine phosphatase dephosphorylates HoxA10 in undifferentiated myeloid cells, maintaining it in a non-phosphorylated state that sustains repression of CYBB and NCF2 transcription; constitutively active SHP2 mutants dephosphorylate HoxA10 throughout differentiation, causing persistent repression.","method":"Co-immunoprecipitation, phosphatase activity assays, reporter assays, expression of constitutively active SHP2 mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — biochemical identification of HoxA10 as SHP2 substrate with functional consequence on target gene transcription","pmids":["17138561"],"is_preprint":false},{"year":2008,"finding":"Constitutively active SHP2 cooperates with HoxA10 overexpression to accelerate progression to AML in a murine bone marrow model; SHP2-mediated HoxA10 dephosphorylation throughout myelopoiesis sustains repression of gp91PHOX/p67PHOX genes and activation of DUSP4 (encoding anti-apoptotic Mkp2).","method":"Murine bone marrow transplantation, retroviral co-expression, gene expression assays, reporter assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo AML model with mechanistic epistasis; single lab","pmids":["19022774"],"is_preprint":false},{"year":2010,"finding":"Pbx1 forms a complex at osteoblast-related gene promoters (osteocalcin, bone sialoprotein) that includes histone deacetylases, blocking Hoxa10-mediated chromatin hyperacetylation and CBP/p300 recruitment; knockdown of Pbx1 increases H3K9 acetylation and H4 acetylation at these promoters, enhancing osteogenic gene expression.","method":"ChIP, shRNA knockdown, reporter assays with Pbx-site mutations, overexpression in mesenchymal cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP at endogenous loci, mutagenesis, and shRNA with defined chromatin readout; mechanistically precise","pmids":["20439491"],"is_preprint":false},{"year":2011,"finding":"HoxA10 directly activates transcription of ARIH2 (encoding the E3 ubiquitin ligase Triad1) via two cis elements in the ARIH2 promoter in myeloid cells, leading to increased protein ubiquitination in HoxA10-overexpressing cells; Triad1 knockdown further increased cytokine-induced proliferation, identifying ARIH2/Triad1 as a HoxA10 target that antagonizes myeloproliferation.","method":"Promoter reporter assays, ChIP, Triad1 knockdown, ubiquitination assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — direct promoter binding shown by ChIP, functional rescue with Triad1 knockdown","pmids":["21454682"],"is_preprint":false},{"year":2011,"finding":"HoxA10 activates CDX4 transcription via a HoxA10-binding cis element in the CDX4 promoter; Cdx4 in turn activates the HOXA10 promoter via a Cdx4-binding cis element, establishing a positive feedback loop; Cdx4 knockdown decreased cytokine hypersensitivity of HoxA10-overexpressing myeloid progenitors.","method":"Reporter assays, ChIP, CDX4 promoter mutagenesis, Cdx4 shRNA knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — reciprocal transcriptional regulation confirmed by ChIP and promoter mutagenesis","pmids":["21471217"],"is_preprint":false},{"year":2012,"finding":"HoxA10 directly activates transcription of FGF2 via two cis elements in the proximal FGF2 promoter in myeloid progenitor cells; HoxA10-overexpressing cells showed increased Fgf2 secretion that drove autocrine PI3K-dependent β-catenin increase and cytokine hypersensitivity.","method":"Reporter assays, ChIP, Fgf2 neutralization, PI3K inhibition, proliferation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP, promoter reporter assays, and signaling pathway rescue","pmids":["22493287"],"is_preprint":false},{"year":2013,"finding":"PCAF acetyltransferase directly interacts with HOXA10 and acetylates it at lysine residues K338 and K339, which inhibits HOXA10-mediated transcription of ITGB3 (β3-integrin) and impairs embryo adhesiveness in Ishikawa endometrial cells; PCAF expression is aberrantly high in endometriosis.","method":"Co-immunoprecipitation, Western blotting, confocal immunofluorescence, luciferase reporter, ChIP, BeWo spheroid attachment assay, site-specific mutagenesis","journal":"The Journal of clinical endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 1–2 — biochemical acetylation site identified by mutagenesis, multiple orthogonal methods, functional embryo attachment assay","pmids":["24037888"],"is_preprint":false},{"year":2010,"finding":"HOXA10 directly binds the KLF9 promoter (demonstrated by EMSA) and represses KLF9 transcription specifically in endometrial epithelial cells but not stromal cells; mutation of the HOXA10-binding site abolished both binding and repression in reporter assays.","method":"EMSA, luciferase reporter assay with promoter mutation, siRNA/overexpression, qRT-PCR, immunohistochemistry","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 1–2 — direct DNA binding by EMSA with mutagenesis confirmation and cell-type specificity established","pmids":["20463357"],"is_preprint":false},{"year":2005,"finding":"HOXA9 and HOXA10 overexpression in human CD34+ cord blood cells activated a common transcriptome signature including Wnt pathway genes (Wnt10B, Frizzled 1, Frizzled 5) and other stem-cell genes (ERG, IRX3, ALDH1); HOXA10 specifically repressed heme biosynthesis and globin genes consistent with suppression of erythroid differentiation.","method":"Retroviral transduction of CD34+ cells, cDNA microarray, qRT-PCR validation","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 2 — genome-wide transcriptome with qRT-PCR validation in primary HSCs; single lab","pmids":["15849172"],"is_preprint":false},{"year":2001,"finding":"Retroviral overexpression of HOXA10 in human CD34+ hematopoietic progenitors profoundly impaired myeloid differentiation, almost completely blocked erythroid differentiation, reduced B-cell development by 70% in NOD/SCID mice, and enhanced myelopoiesis with increased blast colony formation.","method":"Retroviral transduction of human cord blood/fetal liver CD34+ cells, in vitro colony assays, NOD/SCID xenograft repopulation","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — human primary cells with both in vitro and in vivo phenotypic readouts; highly cited","pmids":["11290589"],"is_preprint":false},{"year":2012,"finding":"HOXA10 overexpression in human endometrial stromal cells (HESCs) increased FKBP4 (FKBP52) mRNA and protein levels, while HOXA10 knockdown decreased FKBP4 expression; FKBP4 siRNA reduced IGFBP1 expression during decidualization, placing HOXA10 upstream of FKBP4 in the decidualization pathway.","method":"Overexpression, siRNA knockdown, qRT-PCR, Western blotting in HESCs","journal":"Reproduction","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal gain/loss-of-function with epistasis placing HOXA10 upstream of FKBP4; single lab","pmids":["22279148"],"is_preprint":false},{"year":2008,"finding":"HOXA10 transcriptionally regulates Calpain5 in endometrial cells; overexpression of HOXA10 increased Calpain5 expression and siRNA knockdown decreased it, with Calpain5 expression also reduced in endometriosis samples consistent with decreased HOXA10.","method":"Transfection of HOXA10 expression construct and siRNA in HESC and epithelial cells, qRT-PCR, immunohistochemistry","journal":"Molecular human reproduction","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal gain/loss-of-function in human endometrial cells; single lab","pmids":["18829447"],"is_preprint":false},{"year":2018,"finding":"Calpain7 (CAPN7) directly interacts with HOXA10 and degrades it via a PEST sequence in a Ca2+-dependent manner; CAPN7 overexpression reduced HOXA10 protein stability and ITGB3 expression, impairing embryo implantation; calpain inhibitor ALLN reversed CAPN7-induced HOXA10 degradation, and deletion of the PEST motif abolished proteolysis.","method":"Co-immunoprecipitation, Western blot, luciferase reporter, in vivo mouse implantation assay, PEST sequence mutagenesis, ALLN inhibitor rescue","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1–2 — biochemical identification of proteolytic substrate with site-specific mutagenesis and pharmacological rescue in vitro and in vivo","pmids":["29459744"],"is_preprint":false},{"year":2015,"finding":"FoxM1, a Forkhead box transcription factor, acts downstream of Hoxa10 and cyclin D3 during decidualization; conditional FoxM1 deletion in mice caused regional decidualization defects; Hoxa10 regulated transcriptional activity of FoxM1 while cyclin D3 controlled its nuclear translocation in polyploid decidual cells.","method":"Conditional knockout mouse, in vivo and in vitro decidualization assays, cell cycle analysis, nuclear translocation experiments","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with genetic epistasis placing Hoxa10 upstream of FoxM1; single lab","pmids":["26350477"],"is_preprint":false},{"year":2004,"finding":"HOXA10 overexpression in ER-negative BT20 breast cancer cells increased p53 protein expression and reduced invasiveness through Matrigel; estradiol and tamoxifen increased HOXA10 mRNA expression in ER-positive MCF-7 cells.","method":"Stable overexpression, Northern/RT-PCR analysis, Matrigel invasion assay, Western blotting","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2 — gain-of-function with defined molecular (p53 induction) and functional (invasion) phenotype; single lab","pmids":["15044858"],"is_preprint":false},{"year":2006,"finding":"Bisphenol A (BPA) increases HOXA10 expression through two mechanisms: directly via the HOXA10 estrogen response element (ERE) and indirectly via the HOXA10 autoregulatory element (ARE); in utero BPA exposure produces a lasting imprint of HOXA10 expression in adult uterine stroma that becomes uncoupled from estrogen stimulation.","method":"Luciferase reporter assays with ERE/ARE constructs, ER antagonist (ICI) blocking, antisense blocking, in vivo mouse gestational exposure model","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — reporter assays with pharmacological blocking and in vivo confirmation; single lab","pmids":["17093138"],"is_preprint":false},{"year":2011,"finding":"miR-135a and miR-135b directly target HOXA10 via its 3' UTR in endometrial stromal cells; transfection with miR-135a/b decreased HOXA10 mRNA and protein, while inhibitors increased it; luciferase assays confirmed direct binding to the HOXA10 3' UTR in a cell-type-specific manner.","method":"Transfection with miRNA mimics and inhibitors, luciferase reporter with HOXA10 3' UTR, qPCR, Western blot","journal":"The Journal of clinical endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 2 — direct 3' UTR targeting confirmed by luciferase with cell-type specificity; multiple orthogonal methods","pmids":["21956427"],"is_preprint":false},{"year":2015,"finding":"CTCF functions as a negative regulator of HOXA10 promoter activity in breast cancer cells; CTCF occupies the HOXA10 promoter region and maintains H3K27me3 repressive chromatin marks; a 20 bp CTCF binding motif within the HOXA10 promoter was identified by in silico analysis and mutation assay.","method":"CTCF overexpression and knockdown, luciferase reporter with promoter mutations, ChIP for H3K27me3","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and reporter with site-specific mutation; single lab","pmids":["26478432"],"is_preprint":false},{"year":2017,"finding":"In human and baboon decidua, HOXA10 expression decreases after implantation; HOXA10-depleted decidual cells secrete elevated LIF and IL-6, which activate STAT3 (Tyr705) in trophoblast cells to increase MMP expression and TIMP reduction, thereby promoting trophoblast invasion.","method":"HOXA10 depletion in decidual cells, conditioned medium transfer to trophoblast lines, MMP activity assays, STAT3 phosphorylation analysis, STAT3 knockdown rescue","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 — paracrine mechanism defined by conditioned medium experiments with molecular rescue using STAT3 knockdown","pmids":["28520923"],"is_preprint":false},{"year":2010,"finding":"HOXA9 and HOXA10 directly activate ID2 promoter transcription in NK/T-cell lines as shown by ChIP and overexpression experiments; EZH2/PRC2 represses HOXA10 expression in T-cell lines (siRNA knockdown of EZH2 enhanced HOXA10 expression); HOXA10 and ID2 overexpression repressed BIM apoptosis factor expression.","method":"ChIP, promoter reporter assays, siRNA knockdown of EZH2, EZH2 inhibitor (DZNep), overexpression assays","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP-confirmed direct target activation and epigenetic regulation; single lab","pmids":["20565746"],"is_preprint":false},{"year":2015,"finding":"HoxA10 disruption in mice does not significantly alter steady-state granulopoiesis but leads to an overwhelming, fatal emergency granulopoiesis response; re-expression of Triad1 in bone marrow reversed this phenotype, and HoxA9 antagonized ARIH2 transcription opposing HoxA10; differentiation-stage-specific ARIH2 transcription is regulated by tyrosine phosphorylation states of HoxA9 and HoxA10.","method":"HOXA10 knockout mice, emergency granulopoiesis induction, bone marrow retroviral Triad1 rescue, ARIH2 reporter assays, phosphorylation analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 — genetic rescue in vivo and defined epistasis with HoxA9/Triad1","pmids":["25895533"],"is_preprint":false},{"year":2021,"finding":"Hoxa10 expression is maintained by DNA hypermethylation of the Hox-A locus in somite-derived satellite cells (muscle stem cells) in adult mice; Hoxa10 inactivation led to genomic instability and mitotic catastrophe specifically in somite-derived satellite cells but not cranial mesoderm-derived satellite cells, impairing regenerative ability of somite-derived muscles.","method":"Satellite cell-specific conditional Hoxa10 knockout mice, FACS isolation of satellite cells, DNA methylation analysis, genomic instability assays, muscle regeneration assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1–2 — conditional KO with defined cell-autonomous phenotype (mitotic catastrophe) and tissue-specific rescue","pmids":["34108202"],"is_preprint":false},{"year":2021,"finding":"HOXA10 acts as the upstream transcription factor for ALKBH5, forming a regulatory loop; together HOXA10 and ALKBH5 promote m6A demethylation of JAK2 mRNA to activate JAK2/STAT3 signaling and cisplatin resistance in epithelial ovarian cancer cells.","method":"MeRIP-seq, RNA-seq, ChIP, RIP, luciferase reporter, in vivo xenograft, siRNA knockdown","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal genomic and functional approaches; single lab","pmids":["34496932"],"is_preprint":false},{"year":2021,"finding":"HOXA10 enriches at the TGFB2 promoter to promote its transcription, triggering TGFβ/Smad2/3 signaling; Smad proteins in turn upregulate METTL3 expression; METTL3 mediates HOXA10-driven EMT and lung metastasis in gastric cancer cells.","method":"ChIP-qPCR, dual-luciferase reporter, Co-IP, colorimetric m6A assay, in vivo lung metastasis rescue models, Western blot","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP-confirmed direct promoter binding with in vivo rescue; single lab","pmids":["33563300"],"is_preprint":false},{"year":2019,"finding":"HOXA10 knockdown in HCC cells suppresses HDAC1 transcription (via ChIP-confirmed HOXA10 binding at the HDAC1 promoter), increasing p53 acetylation at Lys382, leading to G0/G1 arrest and apoptosis; HDAC1 overexpression rescued the effects of HOXA10 knockdown on proliferation and p53 acetylation.","method":"ChIP, luciferase reporter, flow cytometry, siRNA/shRNA knockdown, HDAC1 rescue overexpression, in vivo xenograft","journal":"Cancer management and research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and epistasis rescue; single lab","pmids":["31440094"],"is_preprint":false},{"year":2009,"finding":"HOXA10 expression in OSE (ovarian surface epithelial) cells promotes homophilic cell adhesion, prevents anoikis, stimulates interactions with extracellular matrix proteins vitronectin and fibronectin, and enhances interaction with omental mesothelial cells and fibroblasts that promotes OSE cell growth.","method":"Stable HOXA10 induction in OSE cells, adhesion assays, anoikis assays, co-culture with omental cells, growth assays","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple cellular functional assays with defined phenotypes; single lab","pmids":["20036708"],"is_preprint":false},{"year":2014,"finding":"HOXA10 overexpression in endometrial cancer cells increases p21 expression, causing G1 phase cell cycle arrest and decreased proliferation; conversely, HOXA10 knockdown decreases p21, with no effect on p16, p27, Myc, cyclins D1/E, CDK2/4/6.","method":"HOXA10 vector transfection and siRNA knockdown, flow cytometry cell cycle analysis, EdU proliferation assay, qRT-PCR and Western blot","journal":"Medical oncology","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal gain/loss-of-function with specific cell cycle readout; single lab","pmids":["24943991"],"is_preprint":false},{"year":2020,"finding":"HOXA10 inhibits osteogenic differentiation of periodontal ligament stem cells (hPDLSCs) by promoting DKK1 expression and reducing nuclear β-catenin, antagonizing Wnt/β-catenin signaling; the Wnt activator LiCl reversed HOXA10 overexpression effects and the Wnt inhibitor ICG-001 reversed HOXA10 knockdown effects.","method":"Overexpression and knockdown of HOXA10 in hPDLSCs, ALP and alizarin red staining, Western blot for β-catenin/DKK1, LiCl and ICG-001 pharmacological rescue","journal":"Connective tissue research","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological epistasis with reciprocal gain/loss-of-function; single lab","pmids":["32299243"],"is_preprint":false}],"current_model":"HOXA10 is a homeodomain transcription factor that directly binds promoter cis-elements to activate or repress target genes (including Runx2, ITGB3, KLF9, FGF2, ARIH2/Triad1, CDX4, HDAC1, TGFB2, and phagocyte oxidase genes) in a cell-type- and differentiation-stage-specific manner; its activity is modulated by post-translational modifications including tyrosine phosphorylation (reducing DNA binding, controlled by SHP2 phosphatase), acetylation by PCAF (inhibiting transcriptional activity), and calpain7-mediated proteolysis via a PEST sequence, and it operates in concert with cofactors including Pbx1/HDAC complexes and chromatin remodeling machinery to regulate uterine receptivity/decidualization, embryo implantation, hematopoietic stem cell self-renewal and myeloid differentiation, osteoblastogenesis, muscle stem cell genomic stability, and tumor progression."},"narrative":{"teleology":[{"year":1995,"claim":"The foundational question of HOXA10's in vivo requirement was answered: Hoxa10 knockout mice revealed essential, non-redundant roles in axial patterning, male gonadal descent, and female fertility, establishing that HOXA10 functions in reproductive tract morphogenesis and implantation.","evidence":"Targeted gene disruption in mice with histological and embryo transfer analysis","pmids":["7700356"],"confidence":"High","gaps":["Molecular targets of HOXA10 in the uterus were unknown","Whether the fertility defect was uterine-autonomous or oviductal was unresolved","No downstream transcriptional targets identified"]},{"year":2000,"claim":"Gain- and loss-of-function experiments in the uterus demonstrated that maternal HOXA10 expression is both necessary and sufficient for implantation efficiency, resolving the question of whether HOXA10 acts at the implantation step rather than earlier embryonic events.","evidence":"In vivo uterine transfection of antisense or expression constructs in pregnant mice","pmids":["10981664"],"confidence":"High","gaps":["Direct transcriptional targets mediating implantation were not identified","Whether HOXA10 acts in epithelium versus stroma was unresolved"]},{"year":2001,"claim":"Retroviral overexpression in human CD34+ cells established that HOXA10 profoundly blocks erythroid and B-cell differentiation while enhancing myeloid blast formation, revealing a dose-dependent role in hematopoietic lineage commitment.","evidence":"Retroviral transduction of human cord blood CD34+ cells with in vitro colony assays and NOD/SCID xenograft repopulation","pmids":["11290589"],"confidence":"High","gaps":["Whether HOXA10 expands true HSCs or committed progenitors was unclear","Direct transcriptional targets in HSCs were unknown"]},{"year":2004,"claim":"HOXA10 was shown to mediate progesterone's effects on endometrial differentiation, as its overexpression in ovariectomized mice phenocopied progesterone-induced calcitonin and prolactin expression, positioning HOXA10 as a critical effector of steroid hormone signaling in the uterus.","evidence":"In vivo uterine transfection in ovariectomized, estrogen-primed mice","pmids":["14648870"],"confidence":"Medium","gaps":["Whether HOXA10 directly activates calcitonin/prolactin promoters was not tested","Upstream regulation of HOXA10 by progesterone receptor was not dissected"]},{"year":2005,"claim":"The mechanism by which HOXA10 controls myeloid differentiation was elucidated: HOXA10 directly represses phagocyte oxidase genes (CYBB, NCF2) by binding their promoters and recruiting HDACs, with tyrosine phosphorylation of the homeodomain relieving repression during differentiation—establishing a post-translational switch controlling HOXA10 DNA-binding activity.","evidence":"Reporter assays, EMSA, ChIP, homeodomain tyrosine mutagenesis, HDAC activity assays in myeloid cells","pmids":["16210632"],"confidence":"High","gaps":["The kinase responsible for homeodomain tyrosine phosphorylation was not identified","Whether tyrosine phosphorylation affects all HOXA10 targets or only phagocyte oxidase genes was unknown"]},{"year":2006,"claim":"SHP2 phosphatase was identified as the enzyme maintaining HOXA10 in its dephosphorylated, DNA-binding-competent state in undifferentiated myeloid cells, and constitutively active SHP2 mutations sustained HOXA10-mediated repression throughout differentiation, linking gain-of-function SHP2 to impaired innate immunity.","evidence":"Co-immunoprecipitation, phosphatase assays, constitutively active SHP2 mutant expression in myeloid cells","pmids":["17138561"],"confidence":"High","gaps":["The specific tyrosine residues dephosphorylated by SHP2 on HOXA10 were not mapped biochemically","In vivo relevance of the SHP2-HOXA10 axis in human myeloid disorders was not established"]},{"year":2006,"claim":"HOXA10 was established as a tumor suppressor in endometrial carcinoma: enforced expression inhibited invasion in vitro and tumor dissemination in vivo by repressing Snail and inducing E-cadherin, while promoter hypermethylation correlated with HOXA10 silencing in advanced tumors.","evidence":"Forced expression in carcinoma lines, nude mouse xenograft, Matrigel invasion, bisulfite sequencing","pmids":["16424022"],"confidence":"High","gaps":["Whether HOXA10 directly binds the Snail promoter was not shown","Causal role of methylation in tumor progression was correlative"]},{"year":2007,"claim":"HOXA10 was shown to directly activate Runx2 and osteoblastic phenotypic genes by binding promoter Hox elements and promoting chromatin hyperacetylation and H3K4 trimethylation, functioning independently of Runx2 in Runx2-null cells—establishing HOXA10 as an autonomous osteogenic transcription factor.","evidence":"Reporter assays, ChIP, siRNA, Runx2-null cell complementation, chromatin modification analysis","pmids":["17325044"],"confidence":"High","gaps":["Identity of the methyltransferase recruited by HOXA10 was unknown","Whether HOXA10 is required for osteoblastogenesis in vivo was not tested"]},{"year":2007,"claim":"A controlled transgenic system demonstrated that intermediate HOXA10 levels expand HSC repopulating capacity ~15-fold while high levels block erythroid/megakaryocyte development, and identified Dkk-1 and Gfi-1 as direct transcriptional targets, resolving the dose-dependent nature of HOXA10 in HSC biology.","evidence":"Doxycycline-inducible transgenic mouse, bone marrow transplantation, ChIP, transcriptional activation assays","pmids":["17234739"],"confidence":"High","gaps":["Mechanism of dose-dependent target selectivity was unknown","Whether Dkk-1 activation mediates HSC expansion was not tested by epistasis"]},{"year":2008,"claim":"SHP2 and HOXA10 were shown to cooperate in AML progression: constitutively active SHP2 sustained HOXA10-mediated repression of gp91PHOX/p67PHOX and activation of the anti-apoptotic phosphatase DUSP4/Mkp2 throughout myelopoiesis, providing a mechanistic basis for leukemogenic synergy.","evidence":"Murine bone marrow transplantation with retroviral co-expression of SHP2 and HOXA10","pmids":["19022774"],"confidence":"Medium","gaps":["Whether DUSP4 is a direct HOXA10 transcriptional target was not confirmed by ChIP","Human AML relevance was not validated"]},{"year":2010,"claim":"The mechanism by which Pbx1 opposes HOXA10 at osteogenic gene promoters was defined: Pbx1 occupies promoters and recruits HDACs that block HOXA10-induced chromatin hyperacetylation and CBP/p300 recruitment, establishing Pbx1 as a chromatin-level antagonist of HOXA10-driven osteoblast differentiation.","evidence":"ChIP, shRNA knockdown of Pbx1, reporter assays with Pbx-site mutations in mesenchymal cells","pmids":["20439491"],"confidence":"High","gaps":["Whether HOXA10 and Pbx1 physically interact or compete for adjacent sites was not resolved","In vivo bone phenotype of Pbx1 loss in osteoblasts was not tested"]},{"year":2011,"claim":"Two new direct transcriptional targets of HOXA10 in myeloid cells were identified—ARIH2/Triad1 (an E3 ubiquitin ligase antagonizing myeloproliferation) and CDX4 (forming a positive feedback loop with HOXA10)—revealing how HOXA10 simultaneously restrains proliferation and amplifies its own signaling circuit.","evidence":"ChIP, promoter reporter assays with cis-element mutagenesis, Triad1 and Cdx4 knockdown in myeloid progenitors","pmids":["21454682","21471217"],"confidence":"High","gaps":["Whether the CDX4-HOXA10 feedback loop operates in vivo in HSCs was not tested","Substrates of Triad1 downstream of HOXA10 were not identified"]},{"year":2012,"claim":"HOXA10 was found to directly activate FGF2 transcription in myeloid progenitors, establishing an autocrine FGF2→PI3K→β-catenin signaling axis that drives cytokine hypersensitivity, linking HOXA10 transcriptional activity to a specific paracrine/autocrine growth factor pathway.","evidence":"ChIP, reporter assays, Fgf2 neutralization, PI3K inhibition, proliferation assays","pmids":["22493287"],"confidence":"High","gaps":["Whether FGF2 activation contributes to HSC expansion or only to myeloid progenitor proliferation was unknown","Role of this axis in AML was not tested"]},{"year":2013,"claim":"The post-translational modification landscape of HOXA10 was expanded: PCAF acetyltransferase was shown to acetylate HOXA10 at K338/K339, inhibiting its transcriptional activation of ITGB3 and impairing embryo adhesion, providing a molecular explanation for reduced endometrial receptivity in endometriosis.","evidence":"Co-IP, site-directed mutagenesis of K338/K339, ChIP, luciferase reporter, BeWo spheroid attachment assay","pmids":["24037888"],"confidence":"High","gaps":["Whether PCAF acetylation affects HOXA10 activity at non-ITGB3 targets was not tested","Deacetylase responsible for reversing HOXA10 acetylation was not identified"]},{"year":2015,"claim":"In vivo rescue experiments in Hoxa10 knockout mice showed that HOXA10 is dispensable for steady-state granulopoiesis but essential for restraining emergency granulopoiesis through Triad1/ARIH2 activation, with re-expression of Triad1 rescuing the lethal phenotype and HoxA9 antagonizing ARIH2 transcription.","evidence":"Hoxa10 knockout mice with emergency granulopoiesis challenge, retroviral Triad1 rescue in bone marrow","pmids":["25895533"],"confidence":"High","gaps":["Mechanism by which emergency signals override HOXA10-Triad1 axis was not defined","Whether HoxA9/HoxA10 ratio determines ARIH2 output in human myeloid cells was not confirmed"]},{"year":2017,"claim":"HOXA10 was found to regulate trophoblast invasion through a paracrine mechanism: its downregulation in decidual cells after implantation increases LIF/IL-6 secretion, activating STAT3 and MMP expression in trophoblasts, revealing a non-cell-autonomous role for HOXA10 decline in implantation progression.","evidence":"HOXA10 depletion in decidual cells, conditioned medium transfer, STAT3 phosphorylation analysis, STAT3 knockdown rescue","pmids":["28520923"],"confidence":"High","gaps":["Whether HOXA10 directly represses LIF and IL-6 promoters was not shown","In vivo validation in implantation models was not performed"]},{"year":2018,"claim":"A proteolytic regulation mechanism was identified: calpain-7 directly cleaves HOXA10 through a PEST sequence in a Ca²⁺-dependent manner, reducing HOXA10 protein stability and ITGB3 expression; PEST deletion abolished degradation, establishing a new post-translational control axis for HOXA10 turnover.","evidence":"Co-IP, PEST mutagenesis, calpain inhibitor ALLN rescue, in vivo mouse implantation assay","pmids":["29459744"],"confidence":"High","gaps":["Physiological signals triggering calpain-7-mediated HOXA10 degradation in the uterus were unknown","Whether calpain-7 regulates HOXA10 in non-uterine contexts was not tested"]},{"year":2021,"claim":"HOXA10 was shown to maintain genomic stability in somite-derived muscle satellite cells; conditional inactivation caused mitotic catastrophe and impaired muscle regeneration specifically in trunk muscles but not cranial-derived muscles, revealing a tissue-of-origin-specific essential function beyond transcriptional regulation of differentiation genes.","evidence":"Satellite cell-specific conditional Hoxa10 knockout mice, FACS, DNA methylation analysis, genomic instability assays, regeneration assays","pmids":["34108202"],"confidence":"High","gaps":["Direct targets mediating genomic stability in satellite cells were not identified","Whether HOXA10 acts through chromatin organization or DNA repair pathways to prevent mitotic catastrophe was unknown"]},{"year":2021,"claim":"In cancer contexts, HOXA10 was linked to epitranscriptomic regulation: it transcriptionally activates ALKBH5 (m6A eraser) in ovarian cancer and TGFB2 in gastric cancer, connecting HOXA10 to m6A-dependent mRNA regulation and TGFβ/Smad-driven EMT pathways.","evidence":"ChIP, MeRIP-seq, RIP, luciferase reporters, in vivo xenograft models","pmids":["34496932","33563300"],"confidence":"Medium","gaps":["Whether HOXA10 regulation of m6A machinery is relevant outside cancer contexts is unknown","Specificity of HOXA10 for ALKBH5 versus other m6A enzymes was not tested","Single-lab findings without independent replication"]},{"year":null,"claim":"A unified structural and genome-wide mechanistic model of HOXA10 target selectivity—explaining how post-translational modifications (phosphorylation, acetylation), cofactor interactions (Pbx1, HDACs, CBP/p300), and chromatin context dictate which genes are activated versus repressed in different cell types—remains to be established.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of HOXA10-DNA or HOXA10-cofactor complexes exists","Genome-wide binding maps (ChIP-seq) across cell types have not been published","How HOXA10 maintains genomic stability in satellite cells at the molecular level is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3,7,15]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,5,7,11,12,13,14,15,31,32]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,7,14,15]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1,2,29]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,1,2,26]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[3,10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,8,28]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,9,30,31]}],"complexes":[],"partners":["PBX1","PTPN11","KAT2B","CAPN7","HDAC1","HOXA9","CDX4"],"other_free_text":[]},"mechanistic_narrative":"HOXA10 is a homeodomain transcription factor that orchestrates cell fate decisions in uterine receptivity, hematopoiesis, osteoblastogenesis, and muscle stem cell maintenance by directly binding promoter cis-elements to activate or repress context-specific target genes. In the uterus, HOXA10 is essential for embryo implantation and decidualization, mediating progesterone-induced endometrial differentiation and regulating targets including ITGB3, KLF9, FKBP4, and FoxM1 [PMID:7700356, PMID:10981664, PMID:14648870, PMID:20463357]. In hematopoietic cells, HOXA10 expands stem cell repopulating capacity at moderate levels while blocking erythroid/megakaryocyte differentiation at high levels, and represses phagocyte oxidase genes (CYBB, NCF2) in undifferentiated myeloid cells through HDAC recruitment—a repression relieved by cytokine-induced tyrosine phosphorylation of the homeodomain and opposed by SHP2 phosphatase-mediated dephosphorylation [PMID:17234739, PMID:16210632, PMID:17138561]. HOXA10 transcriptional activity is further modulated by PCAF-mediated acetylation at K338/K339 that inhibits DNA binding, by calpain-7-dependent proteolytic degradation via a PEST motif, and by Pbx1/HDAC complexes that antagonize HOXA10-driven chromatin hyperacetylation at osteogenic gene promoters [PMID:24037888, PMID:29459744, PMID:20439491]."},"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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to transcriptional activation of HOXA10 and HOXA11 in a subset of T-cell acute lymphoblastic leukemias.","date":"2005","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/15674412","citation_count":90,"is_preprint":false},{"pmid":"11290589","id":"PMC_11290589","title":"Overexpression of HOXA10 perturbs human lymphomyelopoiesis in vitro and in vivo.","date":"2001","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/11290589","citation_count":89,"is_preprint":false},{"pmid":"15576409","id":"PMC_15576409","title":"Retinoic acid signaling acts via Hox1 to establish the posterior limit of the pharynx in the chordate amphioxus.","date":"2004","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/15576409","citation_count":88,"is_preprint":false},{"pmid":"30639311","id":"PMC_30639311","title":"Quercetin inhibits cell viability, migration and invasion by regulating miR-16/HOXA10 axis in oral cancer.","date":"2019","source":"European journal of 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and expression.","date":"1987","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/2891029","citation_count":74,"is_preprint":false},{"pmid":"17173899","id":"PMC_17173899","title":"Salpingectomy increases peri-implantation endometrial HOXA10 expression in women with hydrosalpinx.","date":"2006","source":"Fertility and sterility","url":"https://pubmed.ncbi.nlm.nih.gov/17173899","citation_count":70,"is_preprint":false},{"pmid":"24607788","id":"PMC_24607788","title":"MiR-135a functions as a tumor suppressor in epithelial ovarian cancer and regulates HOXA10 expression.","date":"2014","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/24607788","citation_count":67,"is_preprint":false},{"pmid":"27793380","id":"PMC_27793380","title":"HOXA-10 and E-cadherin expression in the endometrium of women with recurrent implantation failure and recurrent miscarriage.","date":"2016","source":"Fertility and sterility","url":"https://pubmed.ncbi.nlm.nih.gov/27793380","citation_count":66,"is_preprint":false},{"pmid":"15849172","id":"PMC_15849172","title":"Activation of stem-cell specific genes by HOXA9 and HOXA10 homeodomain proteins in CD34+ human cord blood cells.","date":"2005","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/15849172","citation_count":65,"is_preprint":false},{"pmid":"17093138","id":"PMC_17093138","title":"Xenoestrogen exposure imprints expression of genes (Hoxa10) required for normal uterine development.","date":"2006","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/17093138","citation_count":64,"is_preprint":false},{"pmid":"20439491","id":"PMC_20439491","title":"Pbx1 represses osteoblastogenesis by blocking Hoxa10-mediated recruitment of chromatin remodeling factors.","date":"2010","source":"Molecular and cellular 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/19782671","citation_count":24,"is_preprint":false},{"pmid":"14960020","id":"PMC_14960020","title":"Homeobox HOXA10 gene analysis in cryptorchidism.","date":"2004","source":"Journal of pediatric endocrinology & metabolism : JPEM","url":"https://pubmed.ncbi.nlm.nih.gov/14960020","citation_count":24,"is_preprint":false},{"pmid":"21471217","id":"PMC_21471217","title":"HoxA10 activates CDX4 transcription and Cdx4 activates HOXA10 transcription in myeloid cells.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21471217","citation_count":23,"is_preprint":false},{"pmid":"24943991","id":"PMC_24943991","title":"Upregulation HOXA10 homeobox gene in endometrial cancer: role in cell cycle regulation.","date":"2014","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/24943991","citation_count":23,"is_preprint":false},{"pmid":"18701816","id":"PMC_18701816","title":"Molecular switches involving homeodomain proteins, HOXA10 and RUNX2 regulate osteoblastogenesis.","date":"2008","source":"Cells, tissues, organs","url":"https://pubmed.ncbi.nlm.nih.gov/18701816","citation_count":22,"is_preprint":false},{"pmid":"14505762","id":"PMC_14505762","title":"Endometrial HOXA10 expression after controlled ovarian hyperstimulation with recombinant follicle-stimulating hormone.","date":"2003","source":"Fertility and sterility","url":"https://pubmed.ncbi.nlm.nih.gov/14505762","citation_count":22,"is_preprint":false},{"pmid":"16753450","id":"PMC_16753450","title":"Over expression of insulin-like 3 does not prevent cryptorchidism in GNRHR or HOXA10 deficient mice.","date":"2006","source":"The Journal of urology","url":"https://pubmed.ncbi.nlm.nih.gov/16753450","citation_count":22,"is_preprint":false},{"pmid":"29459744","id":"PMC_29459744","title":"Calpain7 impairs embryo implantation by downregulating β3-integrin expression via degradation of HOXA10.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/29459744","citation_count":22,"is_preprint":false},{"pmid":"20463357","id":"PMC_20463357","title":"HOXA10 inhibits Kruppel-like factor 9 expression in the human endometrial epithelium.","date":"2010","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/20463357","citation_count":21,"is_preprint":false},{"pmid":"37629050","id":"PMC_37629050","title":"Expression of HOXA10 Gene in Women with Endometriosis: A Systematic Review.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37629050","citation_count":20,"is_preprint":false},{"pmid":"25895533","id":"PMC_25895533","title":"HoxA10 Terminates Emergency Granulopoiesis by Increasing Expression of Triad1.","date":"2015","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/25895533","citation_count":20,"is_preprint":false},{"pmid":"16551735","id":"PMC_16551735","title":"Thrombin and interleukin-1beta regulate HOXA10 expression in human term decidual cells: implications for preterm labor.","date":"2006","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/16551735","citation_count":20,"is_preprint":false},{"pmid":"31381886","id":"PMC_31381886","title":"Tumor-Promoting Activity of Long Noncoding RNA LINC00466 in Lung Adenocarcinoma via miR-144-Regulated HOXA10 Axis.","date":"2019","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31381886","citation_count":20,"is_preprint":false},{"pmid":"32299243","id":"PMC_32299243","title":"HOXA10 inhibit the osteogenic differentiation of periodontal ligament stem cells by regulating β-catenin localization and DKK1 expression.","date":"2020","source":"Connective tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/32299243","citation_count":20,"is_preprint":false},{"pmid":"29658437","id":"PMC_29658437","title":"Decreased Expression of HOXA10 May Activate the Autophagic Process in Ovarian Endometriosis.","date":"2018","source":"Reproductive sciences (Thousand Oaks, Calif.)","url":"https://pubmed.ncbi.nlm.nih.gov/29658437","citation_count":19,"is_preprint":false},{"pmid":"1348361","id":"PMC_1348361","title":"Hox-1.11 and Hox-4.9 homeobox genes.","date":"1992","source":"Proceedings of the National Academy of Sciences of the United States of 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cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34294084","citation_count":18,"is_preprint":false},{"pmid":"39499452","id":"PMC_39499452","title":"Role of HOXA10 in pathologies of the endometrium.","date":"2024","source":"Reviews in endocrine & metabolic disorders","url":"https://pubmed.ncbi.nlm.nih.gov/39499452","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51737,"output_tokens":8509,"usd":0.141423},"stage2":{"model":"claude-opus-4-6","input_tokens":12342,"output_tokens":5026,"usd":0.28104},"total_usd":0.422463,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"Targeted homozygous mutation of Hoxa10 in mice causes anterior homeotic transformation of lumbar vertebrae, bilateral cryptorchidism with spermatogenesis defects in males, and ~80% sterility in females due to embryo death between days 2.5–3.5 post coitum, coinciding with maternal Hoxa10 expression in distal oviductal and uterine epithelium, establishing a role for Hoxa10 in male and female fertility.\",\n      \"method\": \"Targeted gene disruption (knockout mouse), histology, timed embryo analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — foundational knockout study with multiple orthogonal phenotypic readouts; highly cited\",\n      \"pmids\": [\"7700356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Maternal Hoxa10 expression in the uterus is essential for embryo implantation; antisense oligonucleotide knockdown of Hoxa10 in the uterus significantly reduced implantation sites, while constitutive Hoxa10 overexpression increased litter size.\",\n      \"method\": \"In vivo uterine transfection of DNA/liposome complexes with antisense or expression constructs in day-2 pregnant mice\",\n      \"journal\": \"Gene therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct in vivo gain- and loss-of-function with specific implantation phenotype\",\n      \"pmids\": [\"10981664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In vivo uterine transfection of Hoxa10 in ovariectomized, estrogen-primed mice phenocopied progesterone treatment, inducing epithelial calcitonin and stromal prolactin expression, demonstrating that Hoxa10 mediates progesterone-induced functional differentiation of endometrial epithelium and stroma.\",\n      \"method\": \"In vivo uterine transfection, immunohistochemistry, gene expression analysis in ovariectomized mice\",\n      \"journal\": \"Molecular reproduction and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional experiment with defined cellular outcome; single lab\",\n      \"pmids\": [\"14648870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HOXA10 activates the Runx2 P1 promoter via a Hox core motif element in response to BMP2, and directly activates osteoblastic phenotypic genes (alkaline phosphatase, osteocalcin, bone sialoprotein); HOXA10 promotes chromatin hyperacetylation and H3K4 trimethylation at these gene promoters and can induce osteoblast genes even in Runx2-null cells.\",\n      \"method\": \"Reporter assays, ChIP, siRNA knockdown, exogenous expression, Runx2-null cell complementation, chromatin remodeling assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including ChIP, mutagenesis of cis-elements, reconstitution in null cells\",\n      \"pmids\": [\"17325044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HOXA10 negatively regulates IGFBP1 mRNA expression in human endometrial stromal cells during decidualization; overexpression of HOXA10 decreased IGFBP1 mRNA while siRNA knockdown increased it even in the presence of decidualizing stimuli.\",\n      \"method\": \"Overexpression and siRNA knockdown in human endometrial stromal cells (HSC), qRT-PCR\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal gain/loss-of-function in primary cells with defined transcriptional readout; single lab\",\n      \"pmids\": [\"17350963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Controlled transgenic expression of HOXA10 in mice expanded hematopoietic stem cell (HSC) repopulating capacity ~15-fold after in vitro culture at intermediate levels, while high HOXA10 levels blocked erythroid and megakaryocyte development; HOXA10 binding sites were found in HLF, Dkk-1, and Gata-1, and HOXA10 transcriptionally activated Dkk-1 and Gfi-1.\",\n      \"method\": \"Doxycycline-inducible transgenic mouse model, bone marrow transplantation/repopulation assays, ChIP, transcriptional activation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — dose-controlled transgenic system with multiple phenotypic readouts and direct promoter binding evidence\",\n      \"pmids\": [\"17234739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Enforced HOXA10 expression in endometrial carcinoma cells inhibited invasive behavior in vitro and tumor dissemination in nude mice by inducing E-cadherin expression through down-regulation of Snail; HOXA10 promoter methylation correlated with reduced expression and higher tumor grade.\",\n      \"method\": \"Forced expression in carcinoma cell lines, nude mouse xenograft model, invasion assay, bisulfite sequencing\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo functional experiments with defined mechanistic pathway (HOXA10→repression of Snail→E-cadherin induction)\",\n      \"pmids\": [\"16424022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"HoxA10 represses transcription of CYBB (gp91phox) and NCF2 (p67phox) in undifferentiated myeloid cells by binding homologous cis-elements in these promoters; repression requires histone deacetylase recruitment; phosphorylation of two tyrosine residues in the HoxA10 homeodomain by cytokine-activated pathways decreases DNA binding and abrogates repression during myeloid differentiation.\",\n      \"method\": \"Reporter assays, EMSA, ChIP, mutagenesis of homeodomain tyrosine residues, HDAC activity assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal biochemical methods including mutagenesis and HDAC recruitment; replicated across CYBB and NCF2\",\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 it in a non-phosphorylated state that sustains repression of CYBB and NCF2 transcription; constitutively active SHP2 mutants dephosphorylate HoxA10 throughout differentiation, causing persistent repression.\",\n      \"method\": \"Co-immunoprecipitation, phosphatase activity assays, reporter assays, expression of constitutively active SHP2 mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — biochemical identification of HoxA10 as SHP2 substrate with functional consequence on target gene transcription\",\n      \"pmids\": [\"17138561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Constitutively active SHP2 cooperates with HoxA10 overexpression to accelerate progression to AML in a murine bone marrow model; SHP2-mediated HoxA10 dephosphorylation throughout myelopoiesis sustains repression of gp91PHOX/p67PHOX genes and activation of DUSP4 (encoding anti-apoptotic Mkp2).\",\n      \"method\": \"Murine bone marrow transplantation, retroviral co-expression, gene expression assays, reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo AML model with mechanistic epistasis; single lab\",\n      \"pmids\": [\"19022774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Pbx1 forms a complex at osteoblast-related gene promoters (osteocalcin, bone sialoprotein) that includes histone deacetylases, blocking Hoxa10-mediated chromatin hyperacetylation and CBP/p300 recruitment; knockdown of Pbx1 increases H3K9 acetylation and H4 acetylation at these promoters, enhancing osteogenic gene expression.\",\n      \"method\": \"ChIP, shRNA knockdown, reporter assays with Pbx-site mutations, overexpression in mesenchymal cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP at endogenous loci, mutagenesis, and shRNA with defined chromatin readout; mechanistically precise\",\n      \"pmids\": [\"20439491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HoxA10 directly activates transcription of ARIH2 (encoding the E3 ubiquitin ligase Triad1) via two cis elements in the ARIH2 promoter in myeloid cells, leading to increased protein ubiquitination in HoxA10-overexpressing cells; Triad1 knockdown further increased cytokine-induced proliferation, identifying ARIH2/Triad1 as a HoxA10 target that antagonizes myeloproliferation.\",\n      \"method\": \"Promoter reporter assays, ChIP, Triad1 knockdown, ubiquitination assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct promoter binding shown by ChIP, functional rescue with Triad1 knockdown\",\n      \"pmids\": [\"21454682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HoxA10 activates CDX4 transcription via a HoxA10-binding cis element in the CDX4 promoter; Cdx4 in turn activates the HOXA10 promoter via a Cdx4-binding cis element, establishing a positive feedback loop; Cdx4 knockdown decreased cytokine hypersensitivity of HoxA10-overexpressing myeloid progenitors.\",\n      \"method\": \"Reporter assays, ChIP, CDX4 promoter mutagenesis, Cdx4 shRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reciprocal transcriptional regulation confirmed by ChIP and promoter mutagenesis\",\n      \"pmids\": [\"21471217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HoxA10 directly activates transcription of FGF2 via two cis elements in the proximal FGF2 promoter in myeloid progenitor cells; HoxA10-overexpressing cells showed increased Fgf2 secretion that drove autocrine PI3K-dependent β-catenin increase and cytokine hypersensitivity.\",\n      \"method\": \"Reporter assays, ChIP, Fgf2 neutralization, PI3K inhibition, proliferation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP, promoter reporter assays, and signaling pathway rescue\",\n      \"pmids\": [\"22493287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PCAF acetyltransferase directly interacts with HOXA10 and acetylates it at lysine residues K338 and K339, which inhibits HOXA10-mediated transcription of ITGB3 (β3-integrin) and impairs embryo adhesiveness in Ishikawa endometrial cells; PCAF expression is aberrantly high in endometriosis.\",\n      \"method\": \"Co-immunoprecipitation, Western blotting, confocal immunofluorescence, luciferase reporter, ChIP, BeWo spheroid attachment assay, site-specific mutagenesis\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — biochemical acetylation site identified by mutagenesis, multiple orthogonal methods, functional embryo attachment assay\",\n      \"pmids\": [\"24037888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HOXA10 directly binds the KLF9 promoter (demonstrated by EMSA) and represses KLF9 transcription specifically in endometrial epithelial cells but not stromal cells; mutation of the HOXA10-binding site abolished both binding and repression in reporter assays.\",\n      \"method\": \"EMSA, luciferase reporter assay with promoter mutation, siRNA/overexpression, qRT-PCR, immunohistochemistry\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct DNA binding by EMSA with mutagenesis confirmation and cell-type specificity established\",\n      \"pmids\": [\"20463357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"HOXA9 and HOXA10 overexpression in human CD34+ cord blood cells activated a common transcriptome signature including Wnt pathway genes (Wnt10B, Frizzled 1, Frizzled 5) and other stem-cell genes (ERG, IRX3, ALDH1); HOXA10 specifically repressed heme biosynthesis and globin genes consistent with suppression of erythroid differentiation.\",\n      \"method\": \"Retroviral transduction of CD34+ cells, cDNA microarray, qRT-PCR validation\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide transcriptome with qRT-PCR validation in primary HSCs; single lab\",\n      \"pmids\": [\"15849172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Retroviral overexpression of HOXA10 in human CD34+ hematopoietic progenitors profoundly impaired myeloid differentiation, almost completely blocked erythroid differentiation, reduced B-cell development by 70% in NOD/SCID mice, and enhanced myelopoiesis with increased blast colony formation.\",\n      \"method\": \"Retroviral transduction of human cord blood/fetal liver CD34+ cells, in vitro colony assays, NOD/SCID xenograft repopulation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human primary cells with both in vitro and in vivo phenotypic readouts; highly cited\",\n      \"pmids\": [\"11290589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HOXA10 overexpression in human endometrial stromal cells (HESCs) increased FKBP4 (FKBP52) mRNA and protein levels, while HOXA10 knockdown decreased FKBP4 expression; FKBP4 siRNA reduced IGFBP1 expression during decidualization, placing HOXA10 upstream of FKBP4 in the decidualization pathway.\",\n      \"method\": \"Overexpression, siRNA knockdown, qRT-PCR, Western blotting in HESCs\",\n      \"journal\": \"Reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal gain/loss-of-function with epistasis placing HOXA10 upstream of FKBP4; single lab\",\n      \"pmids\": [\"22279148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HOXA10 transcriptionally regulates Calpain5 in endometrial cells; overexpression of HOXA10 increased Calpain5 expression and siRNA knockdown decreased it, with Calpain5 expression also reduced in endometriosis samples consistent with decreased HOXA10.\",\n      \"method\": \"Transfection of HOXA10 expression construct and siRNA in HESC and epithelial cells, qRT-PCR, immunohistochemistry\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal gain/loss-of-function in human endometrial cells; single lab\",\n      \"pmids\": [\"18829447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Calpain7 (CAPN7) directly interacts with HOXA10 and degrades it via a PEST sequence in a Ca2+-dependent manner; CAPN7 overexpression reduced HOXA10 protein stability and ITGB3 expression, impairing embryo implantation; calpain inhibitor ALLN reversed CAPN7-induced HOXA10 degradation, and deletion of the PEST motif abolished proteolysis.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, luciferase reporter, in vivo mouse implantation assay, PEST sequence mutagenesis, ALLN inhibitor rescue\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — biochemical identification of proteolytic substrate with site-specific mutagenesis and pharmacological rescue in vitro and in vivo\",\n      \"pmids\": [\"29459744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FoxM1, a Forkhead box transcription factor, acts downstream of Hoxa10 and cyclin D3 during decidualization; conditional FoxM1 deletion in mice caused regional decidualization defects; Hoxa10 regulated transcriptional activity of FoxM1 while cyclin D3 controlled its nuclear translocation in polyploid decidual cells.\",\n      \"method\": \"Conditional knockout mouse, in vivo and in vitro decidualization assays, cell cycle analysis, nuclear translocation experiments\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with genetic epistasis placing Hoxa10 upstream of FoxM1; single lab\",\n      \"pmids\": [\"26350477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"HOXA10 overexpression in ER-negative BT20 breast cancer cells increased p53 protein expression and reduced invasiveness through Matrigel; estradiol and tamoxifen increased HOXA10 mRNA expression in ER-positive MCF-7 cells.\",\n      \"method\": \"Stable overexpression, Northern/RT-PCR analysis, Matrigel invasion assay, Western blotting\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function with defined molecular (p53 induction) and functional (invasion) phenotype; single lab\",\n      \"pmids\": [\"15044858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Bisphenol A (BPA) increases HOXA10 expression through two mechanisms: directly via the HOXA10 estrogen response element (ERE) and indirectly via the HOXA10 autoregulatory element (ARE); in utero BPA exposure produces a lasting imprint of HOXA10 expression in adult uterine stroma that becomes uncoupled from estrogen stimulation.\",\n      \"method\": \"Luciferase reporter assays with ERE/ARE constructs, ER antagonist (ICI) blocking, antisense blocking, in vivo mouse gestational exposure model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assays with pharmacological blocking and in vivo confirmation; single lab\",\n      \"pmids\": [\"17093138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"miR-135a and miR-135b directly target HOXA10 via its 3' UTR in endometrial stromal cells; transfection with miR-135a/b decreased HOXA10 mRNA and protein, while inhibitors increased it; luciferase assays confirmed direct binding to the HOXA10 3' UTR in a cell-type-specific manner.\",\n      \"method\": \"Transfection with miRNA mimics and inhibitors, luciferase reporter with HOXA10 3' UTR, qPCR, Western blot\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct 3' UTR targeting confirmed by luciferase with cell-type specificity; multiple orthogonal methods\",\n      \"pmids\": [\"21956427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CTCF functions as a negative regulator of HOXA10 promoter activity in breast cancer cells; CTCF occupies the HOXA10 promoter region and maintains H3K27me3 repressive chromatin marks; a 20 bp CTCF binding motif within the HOXA10 promoter was identified by in silico analysis and mutation assay.\",\n      \"method\": \"CTCF overexpression and knockdown, luciferase reporter with promoter mutations, ChIP for H3K27me3\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter with site-specific mutation; single lab\",\n      \"pmids\": [\"26478432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In human and baboon decidua, HOXA10 expression decreases after implantation; HOXA10-depleted decidual cells secrete elevated LIF and IL-6, which activate STAT3 (Tyr705) in trophoblast cells to increase MMP expression and TIMP reduction, thereby promoting trophoblast invasion.\",\n      \"method\": \"HOXA10 depletion in decidual cells, conditioned medium transfer to trophoblast lines, MMP activity assays, STAT3 phosphorylation analysis, STAT3 knockdown rescue\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — paracrine mechanism defined by conditioned medium experiments with molecular rescue using STAT3 knockdown\",\n      \"pmids\": [\"28520923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HOXA9 and HOXA10 directly activate ID2 promoter transcription in NK/T-cell lines as shown by ChIP and overexpression experiments; EZH2/PRC2 represses HOXA10 expression in T-cell lines (siRNA knockdown of EZH2 enhanced HOXA10 expression); HOXA10 and ID2 overexpression repressed BIM apoptosis factor expression.\",\n      \"method\": \"ChIP, promoter reporter assays, siRNA knockdown of EZH2, EZH2 inhibitor (DZNep), overexpression assays\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-confirmed direct target activation and epigenetic regulation; single lab\",\n      \"pmids\": [\"20565746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HoxA10 disruption in mice does not significantly alter steady-state granulopoiesis but leads to an overwhelming, fatal emergency granulopoiesis response; re-expression of Triad1 in bone marrow reversed this phenotype, and HoxA9 antagonized ARIH2 transcription opposing HoxA10; differentiation-stage-specific ARIH2 transcription is regulated by tyrosine phosphorylation states of HoxA9 and HoxA10.\",\n      \"method\": \"HOXA10 knockout mice, emergency granulopoiesis induction, bone marrow retroviral Triad1 rescue, ARIH2 reporter assays, phosphorylation analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genetic rescue in vivo and defined epistasis with HoxA9/Triad1\",\n      \"pmids\": [\"25895533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Hoxa10 expression is maintained by DNA hypermethylation of the Hox-A locus in somite-derived satellite cells (muscle stem cells) in adult mice; Hoxa10 inactivation led to genomic instability and mitotic catastrophe specifically in somite-derived satellite cells but not cranial mesoderm-derived satellite cells, impairing regenerative ability of somite-derived muscles.\",\n      \"method\": \"Satellite cell-specific conditional Hoxa10 knockout mice, FACS isolation of satellite cells, DNA methylation analysis, genomic instability assays, muscle regeneration assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — conditional KO with defined cell-autonomous phenotype (mitotic catastrophe) and tissue-specific rescue\",\n      \"pmids\": [\"34108202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HOXA10 acts as the upstream transcription factor for ALKBH5, forming a regulatory loop; together HOXA10 and ALKBH5 promote m6A demethylation of JAK2 mRNA to activate JAK2/STAT3 signaling and cisplatin resistance in epithelial ovarian cancer cells.\",\n      \"method\": \"MeRIP-seq, RNA-seq, ChIP, RIP, luciferase reporter, in vivo xenograft, siRNA knockdown\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal genomic and functional approaches; single lab\",\n      \"pmids\": [\"34496932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HOXA10 enriches at the TGFB2 promoter to promote its transcription, triggering TGFβ/Smad2/3 signaling; Smad proteins in turn upregulate METTL3 expression; METTL3 mediates HOXA10-driven EMT and lung metastasis in gastric cancer cells.\",\n      \"method\": \"ChIP-qPCR, dual-luciferase reporter, Co-IP, colorimetric m6A assay, in vivo lung metastasis rescue models, Western blot\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-confirmed direct promoter binding with in vivo rescue; single lab\",\n      \"pmids\": [\"33563300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HOXA10 knockdown in HCC cells suppresses HDAC1 transcription (via ChIP-confirmed HOXA10 binding at the HDAC1 promoter), increasing p53 acetylation at Lys382, leading to G0/G1 arrest and apoptosis; HDAC1 overexpression rescued the effects of HOXA10 knockdown on proliferation and p53 acetylation.\",\n      \"method\": \"ChIP, luciferase reporter, flow cytometry, siRNA/shRNA knockdown, HDAC1 rescue overexpression, in vivo xenograft\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and epistasis rescue; single lab\",\n      \"pmids\": [\"31440094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"HOXA10 expression in OSE (ovarian surface epithelial) cells promotes homophilic cell adhesion, prevents anoikis, stimulates interactions with extracellular matrix proteins vitronectin and fibronectin, and enhances interaction with omental mesothelial cells and fibroblasts that promotes OSE cell growth.\",\n      \"method\": \"Stable HOXA10 induction in OSE cells, adhesion assays, anoikis assays, co-culture with omental cells, growth assays\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple cellular functional assays with defined phenotypes; single lab\",\n      \"pmids\": [\"20036708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HOXA10 overexpression in endometrial cancer cells increases p21 expression, causing G1 phase cell cycle arrest and decreased proliferation; conversely, HOXA10 knockdown decreases p21, with no effect on p16, p27, Myc, cyclins D1/E, CDK2/4/6.\",\n      \"method\": \"HOXA10 vector transfection and siRNA knockdown, flow cytometry cell cycle analysis, EdU proliferation assay, qRT-PCR and Western blot\",\n      \"journal\": \"Medical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal gain/loss-of-function with specific cell cycle readout; single lab\",\n      \"pmids\": [\"24943991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HOXA10 inhibits osteogenic differentiation of periodontal ligament stem cells (hPDLSCs) by promoting DKK1 expression and reducing nuclear β-catenin, antagonizing Wnt/β-catenin signaling; the Wnt activator LiCl reversed HOXA10 overexpression effects and the Wnt inhibitor ICG-001 reversed HOXA10 knockdown effects.\",\n      \"method\": \"Overexpression and knockdown of HOXA10 in hPDLSCs, ALP and alizarin red staining, Western blot for β-catenin/DKK1, LiCl and ICG-001 pharmacological rescue\",\n      \"journal\": \"Connective tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological epistasis with reciprocal gain/loss-of-function; single lab\",\n      \"pmids\": [\"32299243\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HOXA10 is a homeodomain transcription factor that directly binds promoter cis-elements to activate or repress target genes (including Runx2, ITGB3, KLF9, FGF2, ARIH2/Triad1, CDX4, HDAC1, TGFB2, and phagocyte oxidase genes) in a cell-type- and differentiation-stage-specific manner; its activity is modulated by post-translational modifications including tyrosine phosphorylation (reducing DNA binding, controlled by SHP2 phosphatase), acetylation by PCAF (inhibiting transcriptional activity), and calpain7-mediated proteolysis via a PEST sequence, and it operates in concert with cofactors including Pbx1/HDAC complexes and chromatin remodeling machinery to regulate uterine receptivity/decidualization, embryo implantation, hematopoietic stem cell self-renewal and myeloid differentiation, osteoblastogenesis, muscle stem cell genomic stability, and tumor progression.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"HOXA10 is a homeodomain transcription factor that orchestrates cell fate decisions in uterine receptivity, hematopoiesis, osteoblastogenesis, and muscle stem cell maintenance by directly binding promoter cis-elements to activate or repress context-specific target genes. In the uterus, HOXA10 is essential for embryo implantation and decidualization, mediating progesterone-induced endometrial differentiation and regulating targets including ITGB3, KLF9, FKBP4, and FoxM1 [PMID:7700356, PMID:10981664, PMID:14648870, PMID:20463357]. In hematopoietic cells, HOXA10 expands stem cell repopulating capacity at moderate levels while blocking erythroid/megakaryocyte differentiation at high levels, and represses phagocyte oxidase genes (CYBB, NCF2) in undifferentiated myeloid cells through HDAC recruitment—a repression relieved by cytokine-induced tyrosine phosphorylation of the homeodomain and opposed by SHP2 phosphatase-mediated dephosphorylation [PMID:17234739, PMID:16210632, PMID:17138561]. HOXA10 transcriptional activity is further modulated by PCAF-mediated acetylation at K338/K339 that inhibits DNA binding, by calpain-7-dependent proteolytic degradation via a PEST motif, and by Pbx1/HDAC complexes that antagonize HOXA10-driven chromatin hyperacetylation at osteogenic gene promoters [PMID:24037888, PMID:29459744, PMID:20439491].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"The foundational question of HOXA10's in vivo requirement was answered: Hoxa10 knockout mice revealed essential, non-redundant roles in axial patterning, male gonadal descent, and female fertility, establishing that HOXA10 functions in reproductive tract morphogenesis and implantation.\",\n      \"evidence\": \"Targeted gene disruption in mice with histological and embryo transfer analysis\",\n      \"pmids\": [\"7700356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular targets of HOXA10 in the uterus were unknown\", \"Whether the fertility defect was uterine-autonomous or oviductal was unresolved\", \"No downstream transcriptional targets identified\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Gain- and loss-of-function experiments in the uterus demonstrated that maternal HOXA10 expression is both necessary and sufficient for implantation efficiency, resolving the question of whether HOXA10 acts at the implantation step rather than earlier embryonic events.\",\n      \"evidence\": \"In vivo uterine transfection of antisense or expression constructs in pregnant mice\",\n      \"pmids\": [\"10981664\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets mediating implantation were not identified\", \"Whether HOXA10 acts in epithelium versus stroma was unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Retroviral overexpression in human CD34+ cells established that HOXA10 profoundly blocks erythroid and B-cell differentiation while enhancing myeloid blast formation, revealing a dose-dependent role in hematopoietic lineage commitment.\",\n      \"evidence\": \"Retroviral transduction of human cord blood CD34+ cells with in vitro colony assays and NOD/SCID xenograft repopulation\",\n      \"pmids\": [\"11290589\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HOXA10 expands true HSCs or committed progenitors was unclear\", \"Direct transcriptional targets in HSCs were unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"HOXA10 was shown to mediate progesterone's effects on endometrial differentiation, as its overexpression in ovariectomized mice phenocopied progesterone-induced calcitonin and prolactin expression, positioning HOXA10 as a critical effector of steroid hormone signaling in the uterus.\",\n      \"evidence\": \"In vivo uterine transfection in ovariectomized, estrogen-primed mice\",\n      \"pmids\": [\"14648870\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HOXA10 directly activates calcitonin/prolactin promoters was not tested\", \"Upstream regulation of HOXA10 by progesterone receptor was not dissected\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"The mechanism by which HOXA10 controls myeloid differentiation was elucidated: HOXA10 directly represses phagocyte oxidase genes (CYBB, NCF2) by binding their promoters and recruiting HDACs, with tyrosine phosphorylation of the homeodomain relieving repression during differentiation—establishing a post-translational switch controlling HOXA10 DNA-binding activity.\",\n      \"evidence\": \"Reporter assays, EMSA, ChIP, homeodomain tyrosine mutagenesis, HDAC activity assays in myeloid cells\",\n      \"pmids\": [\"16210632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The kinase responsible for homeodomain tyrosine phosphorylation was not identified\", \"Whether tyrosine phosphorylation affects all HOXA10 targets or only phagocyte oxidase genes was unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"SHP2 phosphatase was identified as the enzyme maintaining HOXA10 in its dephosphorylated, DNA-binding-competent state in undifferentiated myeloid cells, and constitutively active SHP2 mutations sustained HOXA10-mediated repression throughout differentiation, linking gain-of-function SHP2 to impaired innate immunity.\",\n      \"evidence\": \"Co-immunoprecipitation, phosphatase assays, constitutively active SHP2 mutant expression in myeloid cells\",\n      \"pmids\": [\"17138561\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The specific tyrosine residues dephosphorylated by SHP2 on HOXA10 were not mapped biochemically\", \"In vivo relevance of the SHP2-HOXA10 axis in human myeloid disorders was not established\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"HOXA10 was established as a tumor suppressor in endometrial carcinoma: enforced expression inhibited invasion in vitro and tumor dissemination in vivo by repressing Snail and inducing E-cadherin, while promoter hypermethylation correlated with HOXA10 silencing in advanced tumors.\",\n      \"evidence\": \"Forced expression in carcinoma lines, nude mouse xenograft, Matrigel invasion, bisulfite sequencing\",\n      \"pmids\": [\"16424022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HOXA10 directly binds the Snail promoter was not shown\", \"Causal role of methylation in tumor progression was correlative\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"HOXA10 was shown to directly activate Runx2 and osteoblastic phenotypic genes by binding promoter Hox elements and promoting chromatin hyperacetylation and H3K4 trimethylation, functioning independently of Runx2 in Runx2-null cells—establishing HOXA10 as an autonomous osteogenic transcription factor.\",\n      \"evidence\": \"Reporter assays, ChIP, siRNA, Runx2-null cell complementation, chromatin modification analysis\",\n      \"pmids\": [\"17325044\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the methyltransferase recruited by HOXA10 was unknown\", \"Whether HOXA10 is required for osteoblastogenesis in vivo was not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"A controlled transgenic system demonstrated that intermediate HOXA10 levels expand HSC repopulating capacity ~15-fold while high levels block erythroid/megakaryocyte development, and identified Dkk-1 and Gfi-1 as direct transcriptional targets, resolving the dose-dependent nature of HOXA10 in HSC biology.\",\n      \"evidence\": \"Doxycycline-inducible transgenic mouse, bone marrow transplantation, ChIP, transcriptional activation assays\",\n      \"pmids\": [\"17234739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of dose-dependent target selectivity was unknown\", \"Whether Dkk-1 activation mediates HSC expansion was not tested by epistasis\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"SHP2 and HOXA10 were shown to cooperate in AML progression: constitutively active SHP2 sustained HOXA10-mediated repression of gp91PHOX/p67PHOX and activation of the anti-apoptotic phosphatase DUSP4/Mkp2 throughout myelopoiesis, providing a mechanistic basis for leukemogenic synergy.\",\n      \"evidence\": \"Murine bone marrow transplantation with retroviral co-expression of SHP2 and HOXA10\",\n      \"pmids\": [\"19022774\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether DUSP4 is a direct HOXA10 transcriptional target was not confirmed by ChIP\", \"Human AML relevance was not validated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The mechanism by which Pbx1 opposes HOXA10 at osteogenic gene promoters was defined: Pbx1 occupies promoters and recruits HDACs that block HOXA10-induced chromatin hyperacetylation and CBP/p300 recruitment, establishing Pbx1 as a chromatin-level antagonist of HOXA10-driven osteoblast differentiation.\",\n      \"evidence\": \"ChIP, shRNA knockdown of Pbx1, reporter assays with Pbx-site mutations in mesenchymal cells\",\n      \"pmids\": [\"20439491\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HOXA10 and Pbx1 physically interact or compete for adjacent sites was not resolved\", \"In vivo bone phenotype of Pbx1 loss in osteoblasts was not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Two new direct transcriptional targets of HOXA10 in myeloid cells were identified—ARIH2/Triad1 (an E3 ubiquitin ligase antagonizing myeloproliferation) and CDX4 (forming a positive feedback loop with HOXA10)—revealing how HOXA10 simultaneously restrains proliferation and amplifies its own signaling circuit.\",\n      \"evidence\": \"ChIP, promoter reporter assays with cis-element mutagenesis, Triad1 and Cdx4 knockdown in myeloid progenitors\",\n      \"pmids\": [\"21454682\", \"21471217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the CDX4-HOXA10 feedback loop operates in vivo in HSCs was not tested\", \"Substrates of Triad1 downstream of HOXA10 were not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"HOXA10 was found to directly activate FGF2 transcription in myeloid progenitors, establishing an autocrine FGF2→PI3K→β-catenin signaling axis that drives cytokine hypersensitivity, linking HOXA10 transcriptional activity to a specific paracrine/autocrine growth factor pathway.\",\n      \"evidence\": \"ChIP, reporter assays, Fgf2 neutralization, PI3K inhibition, proliferation assays\",\n      \"pmids\": [\"22493287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FGF2 activation contributes to HSC expansion or only to myeloid progenitor proliferation was unknown\", \"Role of this axis in AML was not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The post-translational modification landscape of HOXA10 was expanded: PCAF acetyltransferase was shown to acetylate HOXA10 at K338/K339, inhibiting its transcriptional activation of ITGB3 and impairing embryo adhesion, providing a molecular explanation for reduced endometrial receptivity in endometriosis.\",\n      \"evidence\": \"Co-IP, site-directed mutagenesis of K338/K339, ChIP, luciferase reporter, BeWo spheroid attachment assay\",\n      \"pmids\": [\"24037888\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PCAF acetylation affects HOXA10 activity at non-ITGB3 targets was not tested\", \"Deacetylase responsible for reversing HOXA10 acetylation was not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"In vivo rescue experiments in Hoxa10 knockout mice showed that HOXA10 is dispensable for steady-state granulopoiesis but essential for restraining emergency granulopoiesis through Triad1/ARIH2 activation, with re-expression of Triad1 rescuing the lethal phenotype and HoxA9 antagonizing ARIH2 transcription.\",\n      \"evidence\": \"Hoxa10 knockout mice with emergency granulopoiesis challenge, retroviral Triad1 rescue in bone marrow\",\n      \"pmids\": [\"25895533\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which emergency signals override HOXA10-Triad1 axis was not defined\", \"Whether HoxA9/HoxA10 ratio determines ARIH2 output in human myeloid cells was not confirmed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"HOXA10 was found to regulate trophoblast invasion through a paracrine mechanism: its downregulation in decidual cells after implantation increases LIF/IL-6 secretion, activating STAT3 and MMP expression in trophoblasts, revealing a non-cell-autonomous role for HOXA10 decline in implantation progression.\",\n      \"evidence\": \"HOXA10 depletion in decidual cells, conditioned medium transfer, STAT3 phosphorylation analysis, STAT3 knockdown rescue\",\n      \"pmids\": [\"28520923\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HOXA10 directly represses LIF and IL-6 promoters was not shown\", \"In vivo validation in implantation models was not performed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A proteolytic regulation mechanism was identified: calpain-7 directly cleaves HOXA10 through a PEST sequence in a Ca²⁺-dependent manner, reducing HOXA10 protein stability and ITGB3 expression; PEST deletion abolished degradation, establishing a new post-translational control axis for HOXA10 turnover.\",\n      \"evidence\": \"Co-IP, PEST mutagenesis, calpain inhibitor ALLN rescue, in vivo mouse implantation assay\",\n      \"pmids\": [\"29459744\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological signals triggering calpain-7-mediated HOXA10 degradation in the uterus were unknown\", \"Whether calpain-7 regulates HOXA10 in non-uterine contexts was not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"HOXA10 was shown to maintain genomic stability in somite-derived muscle satellite cells; conditional inactivation caused mitotic catastrophe and impaired muscle regeneration specifically in trunk muscles but not cranial-derived muscles, revealing a tissue-of-origin-specific essential function beyond transcriptional regulation of differentiation genes.\",\n      \"evidence\": \"Satellite cell-specific conditional Hoxa10 knockout mice, FACS, DNA methylation analysis, genomic instability assays, regeneration assays\",\n      \"pmids\": [\"34108202\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct targets mediating genomic stability in satellite cells were not identified\", \"Whether HOXA10 acts through chromatin organization or DNA repair pathways to prevent mitotic catastrophe was unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"In cancer contexts, HOXA10 was linked to epitranscriptomic regulation: it transcriptionally activates ALKBH5 (m6A eraser) in ovarian cancer and TGFB2 in gastric cancer, connecting HOXA10 to m6A-dependent mRNA regulation and TGFβ/Smad-driven EMT pathways.\",\n      \"evidence\": \"ChIP, MeRIP-seq, RIP, luciferase reporters, in vivo xenograft models\",\n      \"pmids\": [\"34496932\", \"33563300\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HOXA10 regulation of m6A machinery is relevant outside cancer contexts is unknown\", \"Specificity of HOXA10 for ALKBH5 versus other m6A enzymes was not tested\", \"Single-lab findings without independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unified structural and genome-wide mechanistic model of HOXA10 target selectivity—explaining how post-translational modifications (phosphorylation, acetylation), cofactor interactions (Pbx1, HDACs, CBP/p300), and chromatin context dictate which genes are activated versus repressed in different cell types—remains to be established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of HOXA10-DNA or HOXA10-cofactor complexes exists\", \"Genome-wide binding maps (ChIP-seq) across cell types have not been published\", \"How HOXA10 maintains genomic stability in satellite cells at the molecular level is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3, 7, 15]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 5, 7, 11, 12, 13, 14, 15, 31, 32]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 7, 14, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0074160\", \"supporting_discovery_ids\": [3, 5, 7, 11, 12, 13, 14, 15, 31, 32]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1, 2, 29]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0, 1, 2, 26]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [3, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 8, 28]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 9, 30, 31]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PBX1\",\n      \"PTPN11\",\n      \"KAT2B\",\n      \"CAPN7\",\n      \"HDAC1\",\n      \"HOXA9\",\n      \"CDX4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}