{"gene":"SOX15","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":2005,"finding":"SOX15 associates with Oct3/4 on DNA sequences containing the octamer motif and Sox-binding site, binds similar DNA sequences as SOX2 but with weaker affinity (shown by gel mobility shift assays and SELEX), and directly binds a Sox consensus binding site within the Hrc gene promoter (shown by chromatin immunoprecipitation) to regulate its transcription in mouse ES cells.","method":"Gel mobility shift assay, SELEX, chromatin immunoprecipitation, DNA microarray","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (EMSA, SELEX, ChIP) in a single rigorous study","pmids":["15863505"],"is_preprint":false},{"year":2000,"finding":"Recombinant SOX15 protein binds a consensus SOX DNA-binding site; overexpression in C2C12 myoblasts specifically inhibits activation of muscle-specific genes and expression of myogenin and MyoD, preventing myotube formation; this repressive function requires the C-terminal domain of SOX15, as a C-terminal truncated form lacks this activity.","method":"Electrophoretic mobility shift assay (EMSA), overexpression with C-terminal truncation mutant, gene expression analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro DNA-binding assay plus domain-mutagenesis with clear cellular phenotype","pmids":["10821863"],"is_preprint":false},{"year":2004,"finding":"Sox15-deficient mice display a marked delay in myoblast differentiation in vitro and attenuated skeletal muscle regeneration after crush injury in vivo; Sox15 loss results in downregulation of MyoD and upregulation of Myf5 in myoblasts, indicating a role in determining early myogenic cell lineages.","method":"Homologous recombination knockout mouse, in vitro differentiation assay, crush injury model, RT-PCR expression analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — clean genetic knockout with defined cellular and molecular phenotype, replicated across in vitro and in vivo settings","pmids":["15367664"],"is_preprint":false},{"year":2007,"finding":"Sox15 binds an evolutionarily conserved site in the Foxk1 promoter and recruits Fhl3 to transcriptionally co-activate Foxk1 gene expression in myogenic progenitor cells; knockdown of Sox15 causes perturbed cell cycle kinetics and decreased Foxk1 expression; Sox15 mutant mice display decreased satellite cell numbers and impaired skeletal muscle regeneration.","method":"Transgenic reporter assay, ChIP, knockdown, transgenic mouse model","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — ChIP demonstrating direct binding plus in vivo genetic model with defined molecular and cellular phenotype","pmids":["17363903"],"is_preprint":false},{"year":2006,"finding":"SOX15 physically interacts with the bHLH transcription factor Hand1 (shown by co-immunoprecipitation in co-transfected 293T cells and in vitro binding), and this interaction enhances Hand1-driven transcription; the enhancement requires both the Hand1-binding region and the transactivation domain of SOX15; SOX15 promotes trophoblast giant cell differentiation in concert with Hand1.","method":"Co-immunoprecipitation (co-transfected 293T cells), in vitro binding, luciferase reporter assay","journal":"Differentiation; research in biological diversity","confidence":"High","confidence_rationale":"Tier 1–2 — physical interaction confirmed by both in vitro and cell-based co-IP plus functional reporter assay with domain mapping","pmids":["16759287"],"is_preprint":false},{"year":2009,"finding":"Stable expression of SOX15 in P19 cells is sufficient to upregulate muscle precursor markers Pax3/7, Meox1, and Foxc1 and maintain cells at the precursor stage while blocking progression to MyoD expression and myotube formation; SOX15 elevates inhibitory factors Msx1 and Id1; expression of a SOX15 dominant-negative protein abolishes Pax3/7, Meox1, MRF, and MHC expression, demonstrating SOX15 is necessary for muscle precursor cell fate acquisition.","method":"Stable gene integration, dominant-negative expression, gene expression analysis","journal":"Stem cells (Dayton, Ohio)","confidence":"Medium","confidence_rationale":"Tier 2 — gain- and loss-of-function with defined molecular phenotype in single study","pmids":["19489079"],"is_preprint":false},{"year":2013,"finding":"Restoration of SOX15 expression in pancreatic cancer cell lines with silenced SOX15 reduces cancer cell viability in vitro and in vivo (xenograft); SOX15 suppresses Wnt/β-catenin signaling activity in pancreatic cancer cells; SOX15 is subject to homozygous deletion and aberrant DNA hypermethylation causing silencing in pancreatic cancer.","method":"Expression restoration in cell lines, in vitro viability assay, xenograft mouse model, DNA methylation profiling, Wnt/β-catenin pathway assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — functional rescue experiments in vitro and in vivo with pathway readout, single lab","pmids":["23318427"],"is_preprint":false},{"year":2015,"finding":"SOX15 is specifically expressed in esophageal and other stratified epithelia; ChIP-seq shows SOX15 binding is highly enriched near esophagus-expressed genes; depletion of SOX15 in human esophageal cells significantly and specifically reduces esophageal transcripts, demonstrating direct transcriptional control of the squamous epithelial gene expression program.","method":"ChIP-seq, siRNA knockdown with transcriptome analysis, immunohistochemistry","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"High","confidence_rationale":"Tier 1–2 — genome-wide ChIP-seq combined with loss-of-function transcriptome analysis establishing direct transcriptional control","pmids":["26516633"],"is_preprint":false},{"year":2019,"finding":"miR-147b directly targets the 3′UTR of SOX15 mRNA to suppress its expression (validated by luciferase reporter assay); decreased SOX15 leads to activation of Wnt/β-catenin signaling and increased thyroid carcinoma cell proliferation and invasion; SOX15 overexpression conversely represses Wnt/β-catenin signaling and impedes tumor growth in vivo.","method":"Luciferase reporter assay (3′UTR targeting), overexpression/knockdown, Wnt pathway Western blot, xenograft mouse model","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — direct 3′UTR targeting validated by reporter assay plus functional in vivo data, single lab","pmids":["31760045"],"is_preprint":false},{"year":2022,"finding":"SOX15 transcriptionally activates AOC1 expression in prostate cancer cells; elevated AOC1 acts on spermidine to activate reactive oxygen species production and ferroptosis, thereby suppressing cancer cell proliferation and migration.","method":"SOX15 overexpression/knockdown, gene expression analysis, ROS assay, functional proliferation/migration assays in vitro and in vivo","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 — transcriptional activation of AOC1 by SOX15 shown by expression experiments with functional downstream ferroptosis readout, single lab","pmids":["35922412"],"is_preprint":false},{"year":2023,"finding":"SOX15 cooperates with ESC-enriched transcriptional coactivators to ensure optimal expression of pluripotency-associated genes; SOX15 depletion compromises fibroblast reprogramming to pluripotency independently of SOX2; SOX15 promotes neural differentiation by directly binding and activating a distal enhancer of the neurogenic regulator Hes5.","method":"SOX15 depletion/overexpression in ESCs, reprogramming assay, ChIP demonstrating direct enhancer binding, neural differentiation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal functional experiments (reprogramming, differentiation, ChIP at Hes5 enhancer) in a single rigorous study","pmids":["36764520"],"is_preprint":false},{"year":2024,"finding":"circVPS8 acts as a scaffold that simultaneously binds MKRN1 and SOX15 in glioblastoma, facilitating MKRN1-mediated ubiquitination and subsequent proteasomal degradation of SOX15; this reduces SOX15 levels and, by competitive binding, redirects MKRN1 away from HNF4A, elevating HNF4A expression; combined decreased SOX15 and increased HNF4A synergistically inhibit ferroptosis in glioblastoma stem cells.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, in vivo glioblastoma model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 — mechanism dissected by Co-IP and ubiquitination assays with in vivo validation, single lab","pmids":["39098847"],"is_preprint":false},{"year":2025,"finding":"SOX15 directly binds the MMP2 gene promoter (demonstrated by ChIP-PCR) and inhibits MMP2 promoter activity (demonstrated by dual-luciferase reporter assay), transcriptionally repressing MMP2 expression; this suppresses vasculogenic mimicry and ovarian cancer progression.","method":"ChIP-PCR, dual-luciferase reporter assay, overexpression/knockdown, xenograft mouse model","journal":"Biology of the cell","confidence":"Medium","confidence_rationale":"Tier 1–2 — direct promoter binding confirmed by ChIP-PCR plus reporter assay, single lab","pmids":["40833191"],"is_preprint":false},{"year":2017,"finding":"Xenopus SoxD/Sox15 (orthologue) directly binds Xanf1/Hesx1 protein (shown by GST pull-down) and co-occupies the Xanf1/Hesx1 promoter with it (shown by EMSA), counteracting the repressive auto-regulatory activity of Xanf1/Hesx1 on its own promoter and thereby cooperating to maintain Xanf1/Hesx1 expression during forebrain development.","method":"GST pull-down, EMSA, luciferase reporter assay","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 1–2 — ortholog (Xenopus SoxD/Sox15); direct protein-protein interaction and DNA co-occupancy established by in vitro assays","pmids":["28918251"],"is_preprint":false},{"year":2020,"finding":"SOX15, when co-expressed with ASF1A and OCT4, orchestrates efficient oocyte-based reprogramming to generate iPSCs; these iPSCs exhibit a distinguishable pluripotent state with higher differentiation capacity than canonical iPSCs, indicating SOX15 operates through a mechanism distinct from standard Yamanaka reprogramming.","method":"Overexpression in human somatic cells, iPSC derivation, molecular profiling of pluripotency state","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2–3 — functional reprogramming with molecular characterization of resulting cell state, single lab","pmids":["32738616"],"is_preprint":false},{"year":2019,"finding":"Depletion of SOX15 protein during human primordial germ cell-like cell (hPGCLC) specification (using auxin-inducible degron) has no effect on day 4 but causes a significant progressive decrease in hPGCLC fraction on days 6 and 8; SOX15 overexpression increases hPGCLC fraction on day 8; qPCR suggests PRDM14 may partially compensate for SOX15 loss, indicating SOX15 maintains rather than specifies germ cell identity.","method":"Auxin-inducible degron protein depletion, ProteoTuner overexpression, flow cytometry, qPCR","journal":"Wellcome open research","confidence":"Medium","confidence_rationale":"Tier 2 — protein-level depletion and overexpression with quantitative flow cytometric readout in defined in vitro model","pmids":["31583280"],"is_preprint":false},{"year":2023,"finding":"miR-1294 directly targets the 3′UTR of SOX15 (validated by luciferase reporter assay) in pediatric acute lymphoblastic leukemia cells, suppressing SOX15 expression and thereby activating Wnt3a/β-catenin signaling to promote ALL cell proliferation and inhibit apoptosis.","method":"miRNA transfection, luciferase reporter assay (3′UTR), siRNA knockdown, Western blot for Wnt pathway proteins","journal":"Zhongguo shi yan xue ye xue za zhi","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single reporter assay for 3′UTR targeting with functional follow-up","pmids":["37096504"],"is_preprint":false}],"current_model":"SOX15 is a high-mobility group (HMG)-box transcription factor that binds SOX consensus DNA sequences (with weaker affinity than SOX2), partners with OCT3/4 and tissue-specific co-factors (Fhl3, Hand1) to regulate target gene transcription (Hrc, Foxk1, Hes5, MMP2, AOC1), is required for skeletal muscle regeneration and myogenic progenitor maintenance, contributes to ES cell pluripotency and neural differentiation, functions as a candidate tumor suppressor in multiple cancers in part by suppressing Wnt/β-catenin signaling, and is itself regulated post-translationally via MKRN1-mediated ubiquitination/degradation and post-transcriptionally by multiple miRNAs (miR-147b, miR-1294) targeting its 3′UTR."},"narrative":{"teleology":[{"year":2000,"claim":"Establishing SOX15 as a DNA-binding transcription factor with a functional role in myogenesis: SOX15 was shown to bind SOX consensus DNA and, through its C-terminal transactivation domain, inhibit muscle-specific gene activation when overexpressed in myoblasts, revealing it as a modulator of the myogenic transcriptional program.","evidence":"EMSA for DNA binding, C-terminal truncation mutant, overexpression in C2C12 myoblasts with myogenin/MyoD readout","pmids":["10821863"],"confidence":"High","gaps":["Overexpression-only design; endogenous function not yet addressed","Whether the repressive effect reflects a physiological role or is an artifact of forced expression was unresolved"]},{"year":2004,"claim":"Genetic loss-of-function confirmed that endogenous Sox15 is required for normal myoblast differentiation and skeletal muscle regeneration, and distinguished its role from other MRFs by showing reciprocal regulation of MyoD and Myf5.","evidence":"Sox15 knockout mouse, in vitro differentiation assay, crush injury model, RT-PCR","pmids":["15367664"],"confidence":"High","gaps":["Direct transcriptional targets mediating the regeneration defect were unknown","Whether Sox15 acts in satellite cells specifically was not determined"]},{"year":2005,"claim":"SOX15's partnership with OCT3/4 and its direct DNA target Hrc were identified, placing SOX15 within the pluripotency transcription factor network and establishing it as a weaker-affinity SOX2 paralogue on composite SOX-octamer elements.","evidence":"EMSA, SELEX, ChIP at Hrc promoter, DNA microarray in mouse ES cells","pmids":["15863505"],"confidence":"High","gaps":["Functional redundancy with SOX2 in pluripotency not directly tested","Genome-wide target map in ES cells was lacking"]},{"year":2006,"claim":"Discovery that SOX15 physically interacts with Hand1 and enhances its transcriptional activity expanded SOX15's role beyond myogenesis to trophoblast differentiation, demonstrating co-factor-dependent functional diversity.","evidence":"Co-immunoprecipitation in 293T cells, in vitro binding, luciferase reporter with domain mapping","pmids":["16759287"],"confidence":"High","gaps":["Endogenous relevance in placental tissue not shown","Whether Hand1-SOX15 co-regulate specific genomic loci was unresolved"]},{"year":2007,"claim":"SOX15 was shown to directly activate Foxk1 transcription by binding its promoter with co-activator Fhl3, and Sox15-mutant mice displayed reduced satellite cell numbers, establishing the molecular mechanism by which SOX15 maintains the myogenic progenitor pool.","evidence":"ChIP at Foxk1 promoter, transgenic reporter, knockdown, Sox15 mutant mouse satellite cell quantification","pmids":["17363903"],"confidence":"High","gaps":["Whether Foxk1 restoration rescues the satellite cell defect was not tested","Mechanism linking SOX15-Foxk1 axis to cell cycle regulation in satellite cells was incomplete"]},{"year":2009,"claim":"SOX15 was shown to be sufficient and necessary for muscle precursor cell fate acquisition—upregulating Pax3/7 and Meox1 while blocking premature MyoD expression—clarifying that SOX15 acts at the progenitor stage rather than during terminal differentiation.","evidence":"Stable SOX15 expression and dominant-negative in P19 cells, gene expression analysis","pmids":["19489079"],"confidence":"Medium","gaps":["P19 embryonal carcinoma cells may not fully recapitulate normal myogenesis","Direct targets mediating Pax3/7 upregulation not identified"]},{"year":2013,"claim":"SOX15 was identified as a candidate tumor suppressor in pancreatic cancer, silenced by homozygous deletion and promoter hypermethylation, with functional restoration reducing viability and suppressing Wnt/β-catenin signaling—extending SOX15 biology from development to cancer.","evidence":"Re-expression in pancreatic cancer cell lines, xenograft, Wnt pathway assay, methylation profiling","pmids":["23318427"],"confidence":"Medium","gaps":["Direct mechanism by which SOX15 suppresses Wnt signaling was not defined","No patient cohort survival analysis provided"]},{"year":2015,"claim":"Genome-wide ChIP-seq revealed SOX15 as a lineage-specific transcriptional regulator of squamous epithelial identity, demonstrating that its binding is enriched near esophagus-expressed genes and is required for their transcription—expanding SOX15's tissue repertoire beyond muscle and ES cells.","evidence":"ChIP-seq, siRNA knockdown with transcriptome analysis in human esophageal cells","pmids":["26516633"],"confidence":"High","gaps":["Whether SOX15 loss causes squamous epithelial pathology in vivo was not tested","Co-factors mediating esophageal specificity were not identified"]},{"year":2017,"claim":"In Xenopus, the SOX15 orthologue SoxD was shown to directly bind Hesx1/Xanf1 protein and co-occupy its promoter, counteracting auto-repression and thereby maintaining forebrain gene expression—providing evidence for a conserved role in anterior neural patterning.","evidence":"GST pull-down, EMSA, luciferase reporter in Xenopus","pmids":["28918251"],"confidence":"Medium","gaps":["Conservation of this mechanism in mammalian forebrain not demonstrated","Orthology between Xenopus SoxD and mammalian SOX15 is supported but not definitive"]},{"year":2019,"claim":"Post-transcriptional regulation of SOX15 was established: miR-147b directly targets the SOX15 3′UTR to suppress its expression, thereby activating Wnt/β-catenin signaling and promoting thyroid carcinoma growth, while SOX15 overexpression reverses this effect.","evidence":"Luciferase 3′UTR reporter, overexpression/knockdown, Wnt pathway Western blot, xenograft","pmids":["31760045"],"confidence":"Medium","gaps":["Whether SOX15 directly binds Wnt pathway gene promoters or acts indirectly remains unclear","Single lab; independent replication in thyroid cancer not reported"]},{"year":2019,"claim":"SOX15 was demonstrated to maintain human primordial germ cell-like cell identity after specification, using acute protein depletion and overexpression, distinguishing it from specification factors and suggesting partial functional compensation by PRDM14.","evidence":"Auxin-inducible degron depletion, ProteoTuner overexpression, flow cytometry in hPGCLC model","pmids":["31583280"],"confidence":"Medium","gaps":["Direct transcriptional targets in germ cells not identified","PRDM14 compensation hypothesis based on qPCR only"]},{"year":2020,"claim":"SOX15's role in reprogramming was further refined: co-expression with ASF1A and OCT4 generated iPSCs with a distinctive pluripotent state and higher differentiation capacity than standard Yamanaka iPSCs, indicating SOX15 engages a mechanistically distinct reprogramming pathway.","evidence":"Human somatic cell reprogramming, iPSC derivation, molecular profiling","pmids":["32738616"],"confidence":"Medium","gaps":["Molecular basis distinguishing SOX15-mediated from SOX2-mediated reprogramming not delineated","Whether this alternative pluripotent state is stable long-term was not assessed"]},{"year":2022,"claim":"A new tumor-suppressive mechanism was uncovered: SOX15 transcriptionally activates AOC1, which metabolizes spermidine to generate ROS and induce ferroptosis in prostate cancer cells, linking SOX15 to metabolic cell death pathways.","evidence":"SOX15 overexpression/knockdown, AOC1 expression analysis, ROS assay, in vitro and in vivo proliferation assays","pmids":["35922412"],"confidence":"Medium","gaps":["Direct ChIP evidence for SOX15 binding at the AOC1 promoter not shown","Whether the ferroptosis link operates in other SOX15-expressing tissues is unknown"]},{"year":2023,"claim":"SOX15 was shown to contribute to ES cell pluripotency independently of SOX2 and to promote neural differentiation by directly binding a distal Hes5 enhancer, resolving its non-redundant role in the SOX family pluripotency network.","evidence":"SOX15 depletion/overexpression in ESCs, reprogramming assay, ChIP at Hes5 enhancer, neural differentiation","pmids":["36764520"],"confidence":"High","gaps":["Full set of SOX15-specific versus SOX2-shared targets not catalogued","Structural basis for SOX15-specific enhancer selectivity unknown"]},{"year":2024,"claim":"Post-translational regulation of SOX15 was elucidated: MKRN1-mediated ubiquitination targets SOX15 for proteasomal degradation, scaffolded by circVPS8 in glioblastoma, with SOX15 depletion cooperating with HNF4A elevation to suppress ferroptosis in glioblastoma stem cells.","evidence":"Co-immunoprecipitation, ubiquitination assay, siRNA, in vivo glioblastoma model","pmids":["39098847"],"confidence":"Medium","gaps":["Whether MKRN1-SOX15 ubiquitination occurs outside the glioblastoma context is unknown","Specific lysine residues on SOX15 targeted for ubiquitination not identified"]},{"year":2025,"claim":"SOX15 was shown to directly bind the MMP2 promoter and repress its transcription, thereby suppressing vasculogenic mimicry in ovarian cancer—adding a specific anti-metastatic transcriptional target to SOX15's tumor-suppressive repertoire.","evidence":"ChIP-PCR, dual-luciferase reporter, overexpression/knockdown, xenograft","pmids":["40833191"],"confidence":"Medium","gaps":["Whether MMP2 repression is a general SOX15 function across cancer types is untested","Mechanism by which SOX15 represses (rather than activates) this particular promoter is unclear"]},{"year":null,"claim":"Key unresolved questions include: the structural basis for SOX15's weaker DNA-binding affinity relative to SOX2 and its distinct enhancer selectivity; the direct mechanism by which SOX15 suppresses Wnt/β-catenin signaling; genome-wide maps of SOX15 targets across its diverse tissue contexts (muscle, germ cells, esophagus, tumors); and the physiological regulation of SOX15 protein turnover beyond glioblastoma.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure of SOX15 HMG domain–DNA complex","Direct Wnt pathway target genes of SOX15 unidentified","No integrative multi-tissue SOX15 cistrome"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1,3,7,12]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3,5,7,9,10,12]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3,7,10]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,3,7,10,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,8,16]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,3,5,15]}],"complexes":[],"partners":["POU5F1","FHL3","HAND1","MKRN1","HESX1"],"other_free_text":[]},"mechanistic_narrative":"SOX15 is an HMG-box transcription factor that regulates cell fate decisions across myogenic, pluripotent, epithelial, and germ cell lineages by binding SOX consensus DNA sequences and partnering with context-specific co-factors. It associates with OCT3/4 on octamer-SOX composite elements in embryonic stem cells to regulate pluripotency-associated genes such as Hrc and the Hes5 enhancer, cooperates with Fhl3 to activate Foxk1 in myogenic progenitors required for satellite cell maintenance and skeletal muscle regeneration, and enhances Hand1-driven transcription during trophoblast differentiation [PMID:15863505, PMID:17363903, PMID:16759287, PMID:36764520]. SOX15 functions as a tumor suppressor in multiple cancers—including pancreatic, thyroid, ovarian, and prostate malignancies—by suppressing Wnt/β-catenin signaling and by directly repressing MMP2 or activating AOC1 to promote ferroptosis, and its expression is silenced by promoter hypermethylation, homozygous deletion, or post-transcriptionally by miR-147b and miR-1294 targeting its 3′UTR [PMID:23318427, PMID:31760045, PMID:40833191, PMID:35922412]. SOX15 protein levels are regulated post-translationally through MKRN1-mediated ubiquitination and proteasomal degradation, a process facilitated by the circular RNA scaffold circVPS8 in glioblastoma [PMID:39098847]."},"prefetch_data":{"uniprot":{"accession":"O60248","full_name":"Transcription factor SOX-15","aliases":["Protein SOX-12","Protein SOX-20","SRY-box transcription factor 15"],"length_aa":233,"mass_kda":25.3,"function":"Transcription factor that binds to DNA at the 5'-AACAATG-3' consensus sequence (By similarity). Acts as a transcriptional activator and repressor (By similarity). Binds synergistically with POU5F1 (OCT3/4) to gene promoters (By similarity). Binds to the FOXK1 promoter and recruits FHL3, resulting in transcriptional activation of FOXK1 which leads to myoblast proliferation (By similarity). Acts as an inhibitor of myoblast differentiation via transcriptional repression which leads to down-regulation of the muscle-specific genes MYOD and MYOG (By similarity). Involved in trophoblast giant cell differentiation via enhancement of HAND1 transcriptional activity (By similarity). Regulates transcription of HRC via binding to it proximal enhancer region (By similarity). Involved in skeletal muscle regeneration (By similarity). Also plays a role in the development of myogenic precursor cells (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O60248/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SOX15","classification":"Not Classified","n_dependent_lines":80,"n_total_lines":1208,"dependency_fraction":0.06622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SOX15","total_profiled":1310},"omim":[{"mim_id":"601297","title":"SRY-BOX 15; SOX15","url":"https://www.omim.org/entry/601297"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nucleoli","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":85.9},{"tissue":"skin 1","ntpm":48.3}],"url":"https://www.proteinatlas.org/search/SOX15"},"hgnc":{"alias_symbol":["SOX27","SOX26"],"prev_symbol":["SOX20"]},"alphafold":{"accession":"O60248","domains":[{"cath_id":"1.20.5","chopping":"84-115","consensus_level":"medium","plddt":97.1428,"start":84,"end":115}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60248","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60248-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60248-F1-predicted_aligned_error_v6.png","plddt_mean":66.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SOX15","jax_strain_url":"https://www.jax.org/strain/search?query=SOX15"},"sequence":{"accession":"O60248","fasta_url":"https://rest.uniprot.org/uniprotkb/O60248.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60248/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60248"}},"corpus_meta":[{"pmid":"15863505","id":"PMC_15863505","title":"Differential roles for Sox15 and Sox2 in transcriptional control in mouse embryonic stem cells.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15863505","citation_count":103,"is_preprint":false},{"pmid":"17363903","id":"PMC_17363903","title":"Sox15 and Fhl3 transcriptionally coactivate Foxk1 and regulate myogenic progenitor cells.","date":"2007","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/17363903","citation_count":66,"is_preprint":false},{"pmid":"15367664","id":"PMC_15367664","title":"Sox15 is required for skeletal muscle regeneration.","date":"2004","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15367664","citation_count":60,"is_preprint":false},{"pmid":"23318427","id":"PMC_23318427","title":"SOX15 is a candidate tumor suppressor in pancreatic cancer with a potential role in Wnt/β-catenin signaling.","date":"2013","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23318427","citation_count":58,"is_preprint":false},{"pmid":"25594027","id":"PMC_25594027","title":"SOX15 and other SOX family members are important mediators of tumorigenesis in multiple cancer types.","date":"2014","source":"Oncoscience","url":"https://pubmed.ncbi.nlm.nih.gov/25594027","citation_count":46,"is_preprint":false},{"pmid":"10821863","id":"PMC_10821863","title":"Muscle differentiation is antagonized by SOX15, a new member of the SOX protein family.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10821863","citation_count":41,"is_preprint":false},{"pmid":"19489079","id":"PMC_19489079","title":"SOX15 and SOX7 differentially regulate the myogenic program in P19 cells.","date":"2009","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/19489079","citation_count":40,"is_preprint":false},{"pmid":"35922412","id":"PMC_35922412","title":"SOX15 transcriptionally increases the function of AOC1 to modulate ferroptosis and progression in prostate cancer.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35922412","citation_count":39,"is_preprint":false},{"pmid":"28092101","id":"PMC_28092101","title":"The cross-regulation between SOX15 and Wnt signaling pathway.","date":"2017","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28092101","citation_count":29,"is_preprint":false},{"pmid":"27881125","id":"PMC_27881125","title":"Enhanced expression of the stemness-related factors OCT4, SOX15 and TWIST1 in ectopic endometrium of endometriosis patients.","date":"2016","source":"Reproductive biology and endocrinology : RB&E","url":"https://pubmed.ncbi.nlm.nih.gov/27881125","citation_count":28,"is_preprint":false},{"pmid":"16759287","id":"PMC_16759287","title":"Sox15 enhances trophoblast giant cell differentiation induced by Hand1 in mouse placenta.","date":"2006","source":"Differentiation; research in biological diversity","url":"https://pubmed.ncbi.nlm.nih.gov/16759287","citation_count":25,"is_preprint":false},{"pmid":"19909824","id":"PMC_19909824","title":"Function and molecular evolution of mammalian Sox15, a singleton in the SoxG group of transcription factors.","date":"2009","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19909824","citation_count":23,"is_preprint":false},{"pmid":"8978787","id":"PMC_8978787","title":"SOX20, a new member of the SOX gene family, is located on chromosome 17p13.","date":"1996","source":"Cytogenetics and cell 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England)","url":"https://pubmed.ncbi.nlm.nih.gov/30019915","citation_count":12,"is_preprint":false},{"pmid":"31760045","id":"PMC_31760045","title":"Downregulation of microR-147b represses the proliferation and invasion of thyroid carcinoma cells by inhibiting Wnt/β-catenin signaling via targeting SOX15.","date":"2019","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/31760045","citation_count":12,"is_preprint":false},{"pmid":"10524236","id":"PMC_10524236","title":"Five different genes, Eif4a1, Cd68, Supl15h, Sox15 and Fxr2h, are clustered in a 40 kb region of mouse chromosome 11.","date":"1999","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/10524236","citation_count":11,"is_preprint":false},{"pmid":"36764520","id":"PMC_36764520","title":"Transcription factor SOX15 regulates stem cell pluripotency and promotes neural fate during differentiation by activating the neurogenic gene Hes5.","date":"2023","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36764520","citation_count":11,"is_preprint":false},{"pmid":"28821564","id":"PMC_28821564","title":"SOX15 regulates proliferation and migration of endometrial cancer cells.","date":"2017","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/28821564","citation_count":9,"is_preprint":false},{"pmid":"18393569","id":"PMC_18393569","title":"Mammalian Sox15 gene: promoter analysis and implications for placental evolution.","date":"2008","source":"Zoological science","url":"https://pubmed.ncbi.nlm.nih.gov/18393569","citation_count":9,"is_preprint":false},{"pmid":"39098847","id":"PMC_39098847","title":"CircVPS8 promotes the malignant phenotype and inhibits ferroptosis of glioma stem cells by acting as a scaffold for MKRN1, SOX15 and HNF4A.","date":"2024","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/39098847","citation_count":8,"is_preprint":false},{"pmid":"32738616","id":"PMC_32738616","title":"Analysis of Menstrual Blood Stromal Cells Reveals SOX15 Triggers Oocyte-Based Human Cell Reprogramming.","date":"2020","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/32738616","citation_count":8,"is_preprint":false},{"pmid":"39863187","id":"PMC_39863187","title":"CircPIK3C3 inhibits hepatocellular carcinoma progression and lenvatinib resistance by suppressing the Wnt/β-catenin pathway via the miR-452-5p/SOX15 axis.","date":"2025","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/39863187","citation_count":7,"is_preprint":false},{"pmid":"30950353","id":"PMC_30950353","title":"Inhibition of SOX15 Sensitizes Esophageal Squamous Carcinoma Cells to Paclitaxel.","date":"2019","source":"Current molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30950353","citation_count":6,"is_preprint":false},{"pmid":"35392235","id":"PMC_35392235","title":"Sox15 Methylation Inhibits Cell Proliferation Through Wnt Signaling in Hepatocellular Carcinoma.","date":"2022","source":"Frontiers in 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cell","url":"https://pubmed.ncbi.nlm.nih.gov/40833191","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.01.646736","title":"Joint profiling of 5mC, 5hmC, and the transcriptome in single cells identifies factors responsible for genome-wide DNA methylation erasure in human primordial germ cell maturation","date":"2025-04-06","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.01.646736","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.10.627788","title":"<i>Sox15</i> is a novel retinal developmental gene that promotes cone photoreceptor differentiation through inhibition of alternative rod photoreceptor fates","date":"2024-12-16","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.10.627788","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17928,"output_tokens":4135,"usd":0.057904},"stage2":{"model":"claude-opus-4-6","input_tokens":7630,"output_tokens":3893,"usd":0.203212},"total_usd":0.261116,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"SOX15 associates with Oct3/4 on DNA sequences containing the octamer motif and Sox-binding site, binds similar DNA sequences as SOX2 but with weaker affinity (shown by gel mobility shift assays and SELEX), and directly binds a Sox consensus binding site within the Hrc gene promoter (shown by chromatin immunoprecipitation) to regulate its transcription in mouse ES cells.\",\n      \"method\": \"Gel mobility shift assay, SELEX, chromatin immunoprecipitation, DNA microarray\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (EMSA, SELEX, ChIP) in a single rigorous study\",\n      \"pmids\": [\"15863505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Recombinant SOX15 protein binds a consensus SOX DNA-binding site; overexpression in C2C12 myoblasts specifically inhibits activation of muscle-specific genes and expression of myogenin and MyoD, preventing myotube formation; this repressive function requires the C-terminal domain of SOX15, as a C-terminal truncated form lacks this activity.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA), overexpression with C-terminal truncation mutant, gene expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro DNA-binding assay plus domain-mutagenesis with clear cellular phenotype\",\n      \"pmids\": [\"10821863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Sox15-deficient mice display a marked delay in myoblast differentiation in vitro and attenuated skeletal muscle regeneration after crush injury in vivo; Sox15 loss results in downregulation of MyoD and upregulation of Myf5 in myoblasts, indicating a role in determining early myogenic cell lineages.\",\n      \"method\": \"Homologous recombination knockout mouse, in vitro differentiation assay, crush injury model, RT-PCR expression analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic knockout with defined cellular and molecular phenotype, replicated across in vitro and in vivo settings\",\n      \"pmids\": [\"15367664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Sox15 binds an evolutionarily conserved site in the Foxk1 promoter and recruits Fhl3 to transcriptionally co-activate Foxk1 gene expression in myogenic progenitor cells; knockdown of Sox15 causes perturbed cell cycle kinetics and decreased Foxk1 expression; Sox15 mutant mice display decreased satellite cell numbers and impaired skeletal muscle regeneration.\",\n      \"method\": \"Transgenic reporter assay, ChIP, knockdown, transgenic mouse model\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrating direct binding plus in vivo genetic model with defined molecular and cellular phenotype\",\n      \"pmids\": [\"17363903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SOX15 physically interacts with the bHLH transcription factor Hand1 (shown by co-immunoprecipitation in co-transfected 293T cells and in vitro binding), and this interaction enhances Hand1-driven transcription; the enhancement requires both the Hand1-binding region and the transactivation domain of SOX15; SOX15 promotes trophoblast giant cell differentiation in concert with Hand1.\",\n      \"method\": \"Co-immunoprecipitation (co-transfected 293T cells), in vitro binding, luciferase reporter assay\",\n      \"journal\": \"Differentiation; research in biological diversity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — physical interaction confirmed by both in vitro and cell-based co-IP plus functional reporter assay with domain mapping\",\n      \"pmids\": [\"16759287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Stable expression of SOX15 in P19 cells is sufficient to upregulate muscle precursor markers Pax3/7, Meox1, and Foxc1 and maintain cells at the precursor stage while blocking progression to MyoD expression and myotube formation; SOX15 elevates inhibitory factors Msx1 and Id1; expression of a SOX15 dominant-negative protein abolishes Pax3/7, Meox1, MRF, and MHC expression, demonstrating SOX15 is necessary for muscle precursor cell fate acquisition.\",\n      \"method\": \"Stable gene integration, dominant-negative expression, gene expression analysis\",\n      \"journal\": \"Stem cells (Dayton, Ohio)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function with defined molecular phenotype in single study\",\n      \"pmids\": [\"19489079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Restoration of SOX15 expression in pancreatic cancer cell lines with silenced SOX15 reduces cancer cell viability in vitro and in vivo (xenograft); SOX15 suppresses Wnt/β-catenin signaling activity in pancreatic cancer cells; SOX15 is subject to homozygous deletion and aberrant DNA hypermethylation causing silencing in pancreatic cancer.\",\n      \"method\": \"Expression restoration in cell lines, in vitro viability assay, xenograft mouse model, DNA methylation profiling, Wnt/β-catenin pathway assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional rescue experiments in vitro and in vivo with pathway readout, single lab\",\n      \"pmids\": [\"23318427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SOX15 is specifically expressed in esophageal and other stratified epithelia; ChIP-seq shows SOX15 binding is highly enriched near esophagus-expressed genes; depletion of SOX15 in human esophageal cells significantly and specifically reduces esophageal transcripts, demonstrating direct transcriptional control of the squamous epithelial gene expression program.\",\n      \"method\": \"ChIP-seq, siRNA knockdown with transcriptome analysis, immunohistochemistry\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genome-wide ChIP-seq combined with loss-of-function transcriptome analysis establishing direct transcriptional control\",\n      \"pmids\": [\"26516633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-147b directly targets the 3′UTR of SOX15 mRNA to suppress its expression (validated by luciferase reporter assay); decreased SOX15 leads to activation of Wnt/β-catenin signaling and increased thyroid carcinoma cell proliferation and invasion; SOX15 overexpression conversely represses Wnt/β-catenin signaling and impedes tumor growth in vivo.\",\n      \"method\": \"Luciferase reporter assay (3′UTR targeting), overexpression/knockdown, Wnt pathway Western blot, xenograft mouse model\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct 3′UTR targeting validated by reporter assay plus functional in vivo data, single lab\",\n      \"pmids\": [\"31760045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SOX15 transcriptionally activates AOC1 expression in prostate cancer cells; elevated AOC1 acts on spermidine to activate reactive oxygen species production and ferroptosis, thereby suppressing cancer cell proliferation and migration.\",\n      \"method\": \"SOX15 overexpression/knockdown, gene expression analysis, ROS assay, functional proliferation/migration assays in vitro and in vivo\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — transcriptional activation of AOC1 by SOX15 shown by expression experiments with functional downstream ferroptosis readout, single lab\",\n      \"pmids\": [\"35922412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SOX15 cooperates with ESC-enriched transcriptional coactivators to ensure optimal expression of pluripotency-associated genes; SOX15 depletion compromises fibroblast reprogramming to pluripotency independently of SOX2; SOX15 promotes neural differentiation by directly binding and activating a distal enhancer of the neurogenic regulator Hes5.\",\n      \"method\": \"SOX15 depletion/overexpression in ESCs, reprogramming assay, ChIP demonstrating direct enhancer binding, neural differentiation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional experiments (reprogramming, differentiation, ChIP at Hes5 enhancer) in a single rigorous study\",\n      \"pmids\": [\"36764520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"circVPS8 acts as a scaffold that simultaneously binds MKRN1 and SOX15 in glioblastoma, facilitating MKRN1-mediated ubiquitination and subsequent proteasomal degradation of SOX15; this reduces SOX15 levels and, by competitive binding, redirects MKRN1 away from HNF4A, elevating HNF4A expression; combined decreased SOX15 and increased HNF4A synergistically inhibit ferroptosis in glioblastoma stem cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, in vivo glioblastoma model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — mechanism dissected by Co-IP and ubiquitination assays with in vivo validation, single lab\",\n      \"pmids\": [\"39098847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SOX15 directly binds the MMP2 gene promoter (demonstrated by ChIP-PCR) and inhibits MMP2 promoter activity (demonstrated by dual-luciferase reporter assay), transcriptionally repressing MMP2 expression; this suppresses vasculogenic mimicry and ovarian cancer progression.\",\n      \"method\": \"ChIP-PCR, dual-luciferase reporter assay, overexpression/knockdown, xenograft mouse model\",\n      \"journal\": \"Biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — direct promoter binding confirmed by ChIP-PCR plus reporter assay, single lab\",\n      \"pmids\": [\"40833191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Xenopus SoxD/Sox15 (orthologue) directly binds Xanf1/Hesx1 protein (shown by GST pull-down) and co-occupies the Xanf1/Hesx1 promoter with it (shown by EMSA), counteracting the repressive auto-regulatory activity of Xanf1/Hesx1 on its own promoter and thereby cooperating to maintain Xanf1/Hesx1 expression during forebrain development.\",\n      \"method\": \"GST pull-down, EMSA, luciferase reporter assay\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — ortholog (Xenopus SoxD/Sox15); direct protein-protein interaction and DNA co-occupancy established by in vitro assays\",\n      \"pmids\": [\"28918251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SOX15, when co-expressed with ASF1A and OCT4, orchestrates efficient oocyte-based reprogramming to generate iPSCs; these iPSCs exhibit a distinguishable pluripotent state with higher differentiation capacity than canonical iPSCs, indicating SOX15 operates through a mechanism distinct from standard Yamanaka reprogramming.\",\n      \"method\": \"Overexpression in human somatic cells, iPSC derivation, molecular profiling of pluripotency state\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — functional reprogramming with molecular characterization of resulting cell state, single lab\",\n      \"pmids\": [\"32738616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Depletion of SOX15 protein during human primordial germ cell-like cell (hPGCLC) specification (using auxin-inducible degron) has no effect on day 4 but causes a significant progressive decrease in hPGCLC fraction on days 6 and 8; SOX15 overexpression increases hPGCLC fraction on day 8; qPCR suggests PRDM14 may partially compensate for SOX15 loss, indicating SOX15 maintains rather than specifies germ cell identity.\",\n      \"method\": \"Auxin-inducible degron protein depletion, ProteoTuner overexpression, flow cytometry, qPCR\",\n      \"journal\": \"Wellcome open research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — protein-level depletion and overexpression with quantitative flow cytometric readout in defined in vitro model\",\n      \"pmids\": [\"31583280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"miR-1294 directly targets the 3′UTR of SOX15 (validated by luciferase reporter assay) in pediatric acute lymphoblastic leukemia cells, suppressing SOX15 expression and thereby activating Wnt3a/β-catenin signaling to promote ALL cell proliferation and inhibit apoptosis.\",\n      \"method\": \"miRNA transfection, luciferase reporter assay (3′UTR), siRNA knockdown, Western blot for Wnt pathway proteins\",\n      \"journal\": \"Zhongguo shi yan xue ye xue za zhi\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single reporter assay for 3′UTR targeting with functional follow-up\",\n      \"pmids\": [\"37096504\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SOX15 is a high-mobility group (HMG)-box transcription factor that binds SOX consensus DNA sequences (with weaker affinity than SOX2), partners with OCT3/4 and tissue-specific co-factors (Fhl3, Hand1) to regulate target gene transcription (Hrc, Foxk1, Hes5, MMP2, AOC1), is required for skeletal muscle regeneration and myogenic progenitor maintenance, contributes to ES cell pluripotency and neural differentiation, functions as a candidate tumor suppressor in multiple cancers in part by suppressing Wnt/β-catenin signaling, and is itself regulated post-translationally via MKRN1-mediated ubiquitination/degradation and post-transcriptionally by multiple miRNAs (miR-147b, miR-1294) targeting its 3′UTR.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SOX15 is an HMG-box transcription factor that regulates cell fate decisions across myogenic, pluripotent, epithelial, and germ cell lineages by binding SOX consensus DNA sequences and partnering with context-specific co-factors. It associates with OCT3/4 on octamer-SOX composite elements in embryonic stem cells to regulate pluripotency-associated genes such as Hrc and the Hes5 enhancer, cooperates with Fhl3 to activate Foxk1 in myogenic progenitors required for satellite cell maintenance and skeletal muscle regeneration, and enhances Hand1-driven transcription during trophoblast differentiation [PMID:15863505, PMID:17363903, PMID:16759287, PMID:36764520]. SOX15 functions as a tumor suppressor in multiple cancers—including pancreatic, thyroid, ovarian, and prostate malignancies—by suppressing Wnt/β-catenin signaling and by directly repressing MMP2 or activating AOC1 to promote ferroptosis, and its expression is silenced by promoter hypermethylation, homozygous deletion, or post-transcriptionally by miR-147b and miR-1294 targeting its 3′UTR [PMID:23318427, PMID:31760045, PMID:40833191, PMID:35922412]. SOX15 protein levels are regulated post-translationally through MKRN1-mediated ubiquitination and proteasomal degradation, a process facilitated by the circular RNA scaffold circVPS8 in glioblastoma [PMID:39098847].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing SOX15 as a DNA-binding transcription factor with a functional role in myogenesis: SOX15 was shown to bind SOX consensus DNA and, through its C-terminal transactivation domain, inhibit muscle-specific gene activation when overexpressed in myoblasts, revealing it as a modulator of the myogenic transcriptional program.\",\n      \"evidence\": \"EMSA for DNA binding, C-terminal truncation mutant, overexpression in C2C12 myoblasts with myogenin/MyoD readout\",\n      \"pmids\": [\"10821863\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Overexpression-only design; endogenous function not yet addressed\", \"Whether the repressive effect reflects a physiological role or is an artifact of forced expression was unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Genetic loss-of-function confirmed that endogenous Sox15 is required for normal myoblast differentiation and skeletal muscle regeneration, and distinguished its role from other MRFs by showing reciprocal regulation of MyoD and Myf5.\",\n      \"evidence\": \"Sox15 knockout mouse, in vitro differentiation assay, crush injury model, RT-PCR\",\n      \"pmids\": [\"15367664\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets mediating the regeneration defect were unknown\", \"Whether Sox15 acts in satellite cells specifically was not determined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"SOX15's partnership with OCT3/4 and its direct DNA target Hrc were identified, placing SOX15 within the pluripotency transcription factor network and establishing it as a weaker-affinity SOX2 paralogue on composite SOX-octamer elements.\",\n      \"evidence\": \"EMSA, SELEX, ChIP at Hrc promoter, DNA microarray in mouse ES cells\",\n      \"pmids\": [\"15863505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional redundancy with SOX2 in pluripotency not directly tested\", \"Genome-wide target map in ES cells was lacking\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Discovery that SOX15 physically interacts with Hand1 and enhances its transcriptional activity expanded SOX15's role beyond myogenesis to trophoblast differentiation, demonstrating co-factor-dependent functional diversity.\",\n      \"evidence\": \"Co-immunoprecipitation in 293T cells, in vitro binding, luciferase reporter with domain mapping\",\n      \"pmids\": [\"16759287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous relevance in placental tissue not shown\", \"Whether Hand1-SOX15 co-regulate specific genomic loci was unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"SOX15 was shown to directly activate Foxk1 transcription by binding its promoter with co-activator Fhl3, and Sox15-mutant mice displayed reduced satellite cell numbers, establishing the molecular mechanism by which SOX15 maintains the myogenic progenitor pool.\",\n      \"evidence\": \"ChIP at Foxk1 promoter, transgenic reporter, knockdown, Sox15 mutant mouse satellite cell quantification\",\n      \"pmids\": [\"17363903\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Foxk1 restoration rescues the satellite cell defect was not tested\", \"Mechanism linking SOX15-Foxk1 axis to cell cycle regulation in satellite cells was incomplete\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"SOX15 was shown to be sufficient and necessary for muscle precursor cell fate acquisition—upregulating Pax3/7 and Meox1 while blocking premature MyoD expression—clarifying that SOX15 acts at the progenitor stage rather than during terminal differentiation.\",\n      \"evidence\": \"Stable SOX15 expression and dominant-negative in P19 cells, gene expression analysis\",\n      \"pmids\": [\"19489079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"P19 embryonal carcinoma cells may not fully recapitulate normal myogenesis\", \"Direct targets mediating Pax3/7 upregulation not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"SOX15 was identified as a candidate tumor suppressor in pancreatic cancer, silenced by homozygous deletion and promoter hypermethylation, with functional restoration reducing viability and suppressing Wnt/β-catenin signaling—extending SOX15 biology from development to cancer.\",\n      \"evidence\": \"Re-expression in pancreatic cancer cell lines, xenograft, Wnt pathway assay, methylation profiling\",\n      \"pmids\": [\"23318427\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism by which SOX15 suppresses Wnt signaling was not defined\", \"No patient cohort survival analysis provided\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Genome-wide ChIP-seq revealed SOX15 as a lineage-specific transcriptional regulator of squamous epithelial identity, demonstrating that its binding is enriched near esophagus-expressed genes and is required for their transcription—expanding SOX15's tissue repertoire beyond muscle and ES cells.\",\n      \"evidence\": \"ChIP-seq, siRNA knockdown with transcriptome analysis in human esophageal cells\",\n      \"pmids\": [\"26516633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SOX15 loss causes squamous epithelial pathology in vivo was not tested\", \"Co-factors mediating esophageal specificity were not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"In Xenopus, the SOX15 orthologue SoxD was shown to directly bind Hesx1/Xanf1 protein and co-occupy its promoter, counteracting auto-repression and thereby maintaining forebrain gene expression—providing evidence for a conserved role in anterior neural patterning.\",\n      \"evidence\": \"GST pull-down, EMSA, luciferase reporter in Xenopus\",\n      \"pmids\": [\"28918251\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conservation of this mechanism in mammalian forebrain not demonstrated\", \"Orthology between Xenopus SoxD and mammalian SOX15 is supported but not definitive\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Post-transcriptional regulation of SOX15 was established: miR-147b directly targets the SOX15 3′UTR to suppress its expression, thereby activating Wnt/β-catenin signaling and promoting thyroid carcinoma growth, while SOX15 overexpression reverses this effect.\",\n      \"evidence\": \"Luciferase 3′UTR reporter, overexpression/knockdown, Wnt pathway Western blot, xenograft\",\n      \"pmids\": [\"31760045\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SOX15 directly binds Wnt pathway gene promoters or acts indirectly remains unclear\", \"Single lab; independent replication in thyroid cancer not reported\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"SOX15 was demonstrated to maintain human primordial germ cell-like cell identity after specification, using acute protein depletion and overexpression, distinguishing it from specification factors and suggesting partial functional compensation by PRDM14.\",\n      \"evidence\": \"Auxin-inducible degron depletion, ProteoTuner overexpression, flow cytometry in hPGCLC model\",\n      \"pmids\": [\"31583280\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional targets in germ cells not identified\", \"PRDM14 compensation hypothesis based on qPCR only\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"SOX15's role in reprogramming was further refined: co-expression with ASF1A and OCT4 generated iPSCs with a distinctive pluripotent state and higher differentiation capacity than standard Yamanaka iPSCs, indicating SOX15 engages a mechanistically distinct reprogramming pathway.\",\n      \"evidence\": \"Human somatic cell reprogramming, iPSC derivation, molecular profiling\",\n      \"pmids\": [\"32738616\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis distinguishing SOX15-mediated from SOX2-mediated reprogramming not delineated\", \"Whether this alternative pluripotent state is stable long-term was not assessed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A new tumor-suppressive mechanism was uncovered: SOX15 transcriptionally activates AOC1, which metabolizes spermidine to generate ROS and induce ferroptosis in prostate cancer cells, linking SOX15 to metabolic cell death pathways.\",\n      \"evidence\": \"SOX15 overexpression/knockdown, AOC1 expression analysis, ROS assay, in vitro and in vivo proliferation assays\",\n      \"pmids\": [\"35922412\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ChIP evidence for SOX15 binding at the AOC1 promoter not shown\", \"Whether the ferroptosis link operates in other SOX15-expressing tissues is unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"SOX15 was shown to contribute to ES cell pluripotency independently of SOX2 and to promote neural differentiation by directly binding a distal Hes5 enhancer, resolving its non-redundant role in the SOX family pluripotency network.\",\n      \"evidence\": \"SOX15 depletion/overexpression in ESCs, reprogramming assay, ChIP at Hes5 enhancer, neural differentiation\",\n      \"pmids\": [\"36764520\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of SOX15-specific versus SOX2-shared targets not catalogued\", \"Structural basis for SOX15-specific enhancer selectivity unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Post-translational regulation of SOX15 was elucidated: MKRN1-mediated ubiquitination targets SOX15 for proteasomal degradation, scaffolded by circVPS8 in glioblastoma, with SOX15 depletion cooperating with HNF4A elevation to suppress ferroptosis in glioblastoma stem cells.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assay, siRNA, in vivo glioblastoma model\",\n      \"pmids\": [\"39098847\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MKRN1-SOX15 ubiquitination occurs outside the glioblastoma context is unknown\", \"Specific lysine residues on SOX15 targeted for ubiquitination not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"SOX15 was shown to directly bind the MMP2 promoter and repress its transcription, thereby suppressing vasculogenic mimicry in ovarian cancer—adding a specific anti-metastatic transcriptional target to SOX15's tumor-suppressive repertoire.\",\n      \"evidence\": \"ChIP-PCR, dual-luciferase reporter, overexpression/knockdown, xenograft\",\n      \"pmids\": [\"40833191\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MMP2 repression is a general SOX15 function across cancer types is untested\", \"Mechanism by which SOX15 represses (rather than activates) this particular promoter is unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis for SOX15's weaker DNA-binding affinity relative to SOX2 and its distinct enhancer selectivity; the direct mechanism by which SOX15 suppresses Wnt/β-catenin signaling; genome-wide maps of SOX15 targets across its diverse tissue contexts (muscle, germ cells, esophagus, tumors); and the physiological regulation of SOX15 protein turnover beyond glioblastoma.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure of SOX15 HMG domain–DNA complex\", \"Direct Wnt pathway target genes of SOX15 unidentified\", \"No integrative multi-tissue SOX15 cistrome\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1, 3, 7, 12]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3, 5, 7, 9, 10, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3, 7, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 3, 7, 10, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 8, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 3, 5, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"POU5F1\",\n      \"FHL3\",\n      \"HAND1\",\n      \"MKRN1\",\n      \"HESX1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}