{"gene":"SOX6","run_date":"2026-06-10T07:46:38","timeline":{"discoveries":[{"year":1998,"finding":"L-Sox5 and Sox6 contain a coiled-coil domain that mediates homodimerization and heterodimerization; dimerization greatly increases efficiency of DNA binding to adjacent HMG sites. L-Sox5, Sox6, and Sox9 cooperatively activate the Col2a1 chondrocyte-specific enhancer by directly binding to HMG-like sites within a 48 bp element.","method":"Protein dimerization assays, DNA binding/EMSA, reporter gene (luciferase) assays in 10T1/2 and MC615 cells, transgenic mouse enhancer analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro binding, dimerization assays, and in vivo transgenic validation in single rigorous study; replicated by multiple subsequent papers","pmids":["9755172"],"is_preprint":false},{"year":2001,"finding":"Sox6 represses transcription from the Fgf-3 promoter through the PS4A regulatory element, and recruits the co-repressor CtBP2 via a short PLNLSS motif in its N-terminal region; mutation of this motif abolishes CtBP2 binding and CtBP2-dependent repression.","method":"Yeast one-hybrid screen, yeast two-hybrid screen, reporter gene assays in NIH3T3 cells, site-directed mutagenesis, co-expression studies, in situ hybridisation","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — yeast two-hybrid confirmed in mammalian cells, mutagenesis of binding motif, reporter assay; single lab but multiple orthogonal methods","pmids":["11504872"],"is_preprint":false},{"year":2002,"finding":"Sox9 is required upstream of Sox5 and Sox6 for their expression in chondrogenic mesenchymal cells; conditional Sox9 inactivation before mesenchymal condensations abolishes Sox5 and Sox6 expression, placing Sox9 upstream in the chondrogenic transcription factor hierarchy.","method":"Cre/loxP conditional knockout mice, in situ hybridisation, immunohistochemistry, genetic epistasis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic epistasis in mouse, replicated across developmental stages, widely cited","pmids":["12414734"],"is_preprint":false},{"year":2003,"finding":"Sox5 and Sox6 are required cell-autonomously for notochord extracellular matrix sheath formation (including Col2a1, aggrecan, perlecan expression), notochord cell survival, and nucleus pulposus development in intervertebral discs; double knockout mice lack nuclei pulposi and show progressive notochord apoptosis.","method":"Sox5/Sox6 double-null mouse genetic analysis, in situ hybridisation, immunohistochemistry, gene expression analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean double KO with specific molecular and cellular phenotype, multiple markers, in vivo","pmids":["12571105"],"is_preprint":false},{"year":2003,"finding":"Sox6 is expressed exclusively during cardiomyocyte commitment in P19CL6 cells, interacts physically with Prtb (Proline-rich transcript of the brain) protein, and represses expression of the L-type Ca2+ channel alpha1c subunit; BMP signaling is required upstream for Sox6 expression in this context.","method":"Yeast two-hybrid, co-immunoprecipitation, P19CL6 cardiomyocyte differentiation model, noggin-expressing stable cells, in vivo comparison of WT vs p100H mutant mice","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — yeast two-hybrid confirmed by Co-IP, functional readout in cell model and in vivo, single lab","pmids":["14530442"],"is_preprint":false},{"year":2005,"finding":"SOX6 acts as a co-repressor of PDX1-mediated insulin gene transcription through a direct protein-protein interaction between the LZ/Q domain of SOX6 and PDX1; SOX6 overexpression reduces histone H3/H4 acetylation at the insulin II promoter, suppressing glucose-stimulated insulin secretion.","method":"siRNA knockdown, retroviral overexpression, luciferase reporter assay, in vitro binding, chromatin immunoprecipitation (ChIP), ATP/ADP ratio, Ca2+ mobilization assays in MIN6 and INS-1E cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct protein interaction mapped to domains, ChIP, functional metabolic readouts, multiple orthogonal methods in single study","pmids":["16148004"],"is_preprint":false},{"year":2006,"finding":"Sox6 directly binds the epsilony-globin proximal promoter (36 bp region) in definitive erythropoiesis and acts as a transcriptional repressor to silence epsilon-globin; loss of Sox6 in p100H mice results in persistent epsilony expression in fetal liver definitive erythrocytes.","method":"EMSA, ChIP, transfection reporter assays in GM979 cells, Sox6-deficient mouse analysis","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct DNA binding shown by EMSA and ChIP, functional repression confirmed in cell and mouse models","pmids":["16462943"],"is_preprint":false},{"year":2006,"finding":"Sox6 cell-autonomously promotes proerythroblast survival and proliferation, facilitates erythroblast maturation (hemoglobinization, condensation, enucleation), and stabilizes F-actin levels in erythroid cells; erythroid-specific inactivation phenocopies germline null, demonstrating cell-autonomous roles.","method":"Erythroid-specific conditional Sox6 knockout (Sox6fl/fl x ErGFPCre), flow cytometry, in vitro EPO signaling assays, F-actin staining, bone marrow and fetal liver analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO with defined molecular (F-actin) and cellular phenotypes; multiple orthogonal assays","pmids":["16627753"],"is_preprint":false},{"year":2006,"finding":"SOX6 transcriptional activity is repressed by SUMO modification at two distinct sites; mutation of both SUMO sites increases SOX6 transcriptional activity; UBC9 promotes SUMO-dependent repression and SUMO protease/siRNA to UBC9 increases activity; SUMO2 co-expression relocalizes SOX6 to punctate nuclear foci colocalizing with PML bodies.","method":"In vitro and in vivo SUMOylation assays, site-directed mutagenesis of SUMO acceptor lysines, reporter gene assays, siRNA, immunofluorescence microscopy","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro and in vivo PTM demonstrated, mutagenesis abolishes modification and shows functional consequence, subcellular localization change documented","pmids":["16442531"],"is_preprint":false},{"year":2007,"finding":"SOX6 suppresses cyclin D1 promoter activity by physically interacting with beta-catenin (via LZ/Q domain binding to armadillo repeats 1-4) and HDAC1; SOX6 overexpression reduces acetylated histones H3 and H4 at the cyclin D1 promoter, inhibiting cell proliferation; SOX6 knockdown stimulates INS-1E and NIH-3T3 cell proliferation.","method":"siRNA, retroviral overexpression, luciferase reporter assay, in vitro binding (GST pulldown), ChIP, HDAC inhibitor, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — domain-mapped protein interaction, ChIP confirming chromatin changes, functional proliferation assays; multiple orthogonal methods single lab","pmids":["17412698"],"is_preprint":false},{"year":2007,"finding":"Sox6 functions as a transcriptional repressor of slow fiber-type specific genes (including MyHC-beta/MyHC-I) in fetal skeletal muscle; Sox6 null mice have all fetal fibers maintaining slow characteristics; a Sox consensus sequence in the MyHC-beta promoter functions as a negative cis-regulatory element bound by Sox6.","method":"Sox6 null mouse phenotype analysis, siRNA knockdown in myotubes, MyHC-beta promoter analysis, reporter assays","journal":"Developmental dynamics","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo null phenotype with molecular promoter analysis and siRNA confirmation; multiple approaches","pmids":["17584907"],"is_preprint":false},{"year":2008,"finding":"L-Sox5/Sox6 enhances Sox9 binding to its recognition site on the Agc1 (aggrecan) far-upstream enhancer by binding to three additional flanking elements, thereby potentiating Sox9 transcriptional activation; L-Sox5/Sox6 similarly secures Sox9 binding at Col2a1 and other cartilage-specific enhancers.","method":"Transgenic mouse enhancer assays, ChIP, EMSA, reporter gene assays, site-directed mutagenesis of cis-elements","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mechanistic ChIP, EMSA, mutagenesis and transgenic validation; multiple orthogonal methods","pmids":["18559420"],"is_preprint":false},{"year":2008,"finding":"Prdm1 promotes slow-twitch muscle fiber differentiation in zebrafish by acting as a transcriptional repressor that directly represses sox6 (shown by ChIP); Prdm1-mediated repression of Sox6 relieves Sox6's repression of slow-fiber-specific genes, thereby enabling slow-twitch gene expression in adaxial cells.","method":"ChIP in zebrafish embryos, ubo mutant analysis, gene expression assays, epistasis","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct ChIP evidence for Prdm1 occupancy at sox6 targets, clear epistatic rescue, zebrafish ortholog","pmids":["18535625"],"is_preprint":false},{"year":2009,"finding":"Sox6 functions downstream of Lhx6 in MGE-derived cortical interneuron development; Sox6 null animals phenocopy Lhx6 null animals with loss of PV and SST expression and mispositioned basket/Martinotti neurons; basket cells in Sox6 mutants retain immature fast-spiking features, indicating Sox6 is required for maturation but not specification.","method":"Sox6 null mouse analysis, electrophysiology, genetic epistasis with Lhx6 null, immunostaining, position analysis","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — null mouse with electrophysiology, epistasis with Lhx6, specific cellular phenotype with molecular markers","pmids":["19709629"],"is_preprint":false},{"year":2009,"finding":"SOX6 controls molecular segregation of dorsal (pallial) from ventral (subpallial) telencephalic progenitors; loss of SOX6 from pallial progenitors causes inappropriate expression of subpallium-restricted developmental controls; SOX6 and SOX5 are mutually exclusively expressed in pallial/subpallial progenitors and in reverse pattern in postmitotic neurons.","method":"Sox6 conditional knockout mice, immunohistochemistry, in situ hybridisation, gene expression profiling","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with specific molecular and cellular phenotype, comparison with Sox5 pattern","pmids":["19657336"],"is_preprint":false},{"year":2009,"finding":"DAX-1 and SOX6 interact physically (confirmed by yeast two-hybrid and biochemical assays) and act antagonistically in pre-mRNA splicing: DAX-1 inhibits splicing in vivo and in vitro, and SOX6 relieves this inhibition by interfering with the DAX-1/splicing machinery interaction.","method":"Yeast two-hybrid, biochemical co-precipitation, in vivo and in vitro splicing assays","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed biochemically, in vitro splicing assay with mechanistic model; single lab","pmids":["19384854"],"is_preprint":false},{"year":2010,"finding":"BCL11A and SOX6 physically interact and co-occupy the human beta-globin cluster along with GATA1, cooperating to silence gamma-globin transcription in adult human erythroid progenitors; BCL11A modulates chromosomal loop formation at the beta-globin locus.","method":"ChIP-chip, chromosome conformation capture (3C), co-immunoprecipitation, siRNA knockdown in adult erythroid progenitors","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — physical interaction by Co-IP, chromatin occupancy by ChIP-chip, loop formation by 3C, functional knockdown; multiple orthogonal methods","pmids":["20395365"],"is_preprint":false},{"year":2010,"finding":"Sox6 directly upregulates Bcl2l1 (encoding anti-apoptotic Bcl-xL) in erythroid cells downstream of erythropoietin signaling; conditional Sox6 inactivation in adult mice causes downregulation of Bcl2l1 and in vitro assays confirm Sox6 direct regulation of this gene.","method":"Conditional Sox6 knockout (Sox6fl/flCaggCreER and Sox6fl/flErGFPCre), tamoxifen induction, gene expression profiling, in vitro erythroblast assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with target gene readout and in vitro confirmation; single lab, molecular target validated but not by direct ChIP in this paper","pmids":["20711497"],"is_preprint":false},{"year":2010,"finding":"A highly conserved double Sox6 binding site within the Sox6 gene promoter mediates negative autoregulation: Sox6 protein binds this site in vitro and in vivo (ChIP), reduces chromatin accessibility, and transcriptionally represses its own gene in erythroid cells.","method":"Bioinformatic genome-wide search, EMSA, ChIP, luciferase reporter assays in K562 and primary erythroblasts, chromatin accessibility (PstI restriction), lentiviral transduction","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro and in vivo binding, ChIP, reporter assays, functional readout; multiple orthogonal methods, single lab","pmids":["20852263"],"is_preprint":false},{"year":2011,"finding":"Sox6 overexpression in human erythroid progenitors (K562 and cord blood CD34+ cells) enhances erythroid differentiation and directly activates SOCS3 expression by binding to a conserved regulatory element in the SOCS3 gene; SOCS3 overexpression recapitulates Sox6-induced growth inhibition.","method":"Lentiviral overexpression in K562 and primary human erythroid cultures, EMSA, ChIP, reporter assays, SOCS3 rescue experiment","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct binding of Sox6 to SOCS3 regulatory element by EMSA and ChIP, functional rescue with SOCS3 overexpression; multiple orthogonal methods","pmids":["21263153"],"is_preprint":false},{"year":2011,"finding":"In mouse fetal myotubes, Sox6 genome-wide binding (ChIP-seq) is predominantly associated with slow fiber-specific, cardiac, and embryonic isoform sarcomere genes as well as muscle developmental transcription factor genes; RNA Pol II ChIP-seq shows 84% of Sox6-bound genes are transcriptionally inactive, confirming Sox6 acts as a direct transcriptional suppressor; muscle-specific Sox6 KO adult mice show dramatic upregulation of these bound genes.","method":"ChIP-seq (Sox6 and RNA Pol II), muscle-specific Sox6 knockout mice, gene expression profiling","journal":"BMC developmental biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genome-wide ChIP-seq with matched RNA Pol II occupancy plus conditional KO; multiple orthogonal methods confirming direct repressor role","pmids":["21985497"],"is_preprint":false},{"year":2011,"finding":"SHOX interacts physically with SOX6 (and SOX5) via the SHOX homeodomain and SOX6 HMG domain; SHOX cooperates with SOX5/SOX6 and SOX9 to activate the upstream Agc1 enhancer; LWD/ISS patient SHOX missense mutations disrupt this interaction and impair Agc1 activation.","method":"Yeast two-hybrid, co-immunoprecipitation in human cells, immunohistochemistry on human fetal growth plate, domain mutagenesis, luciferase reporter assays","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — reciprocal Co-IP, domain mapping, patient mutation disruption, reporter assay; multiple orthogonal methods single lab","pmids":["21262861"],"is_preprint":false},{"year":2011,"finding":"Sox6 transcription in zebrafish slow-twitch progenitors is repressed by Prdm1a transcriptionally; subsequently, miR-499 (whose expression is controlled by Prdm1a) restricts Sox6 protein to fast-twitch fibers by translational repression, forming a regulatory loop that maintains the slow-twitch lineage.","method":"Cis-regulatory reporter transgenics, morpholino knockdown, miR-499 analysis, Prdm1a-dependent expression assays in zebrafish","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — cis-regulatory elements characterised in transgenic fish, Prdm1a-dependence shown, miR-499 translational repression demonstrated; multiple orthogonal methods","pmids":["21880783"],"is_preprint":false},{"year":2012,"finding":"L-Sox5 and Sox6 enhance Sox9 homodimer-mediated transcriptional activation of miR-140, a cartilage-specific microRNA; a Sox trio response element and detailed binding site were mapped in the pri-miR-140 promoter; L-Sox5/Sox6 boost Sox9 DNA binding and/or transactivation as a homodimer.","method":"Transgenic mouse reporter assays, ChIP, reporter gene assays in chondrocyte cell lines, binding site mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vivo transgenic reporter, ChIP, detailed mutagenesis of binding site; multiple methods single lab","pmids":["22547066"],"is_preprint":false},{"year":2014,"finding":"Sox6 selectively marks and specifies substantia nigra (SNc) dopamine neurons; Sox6 ablation decreases SNc marker expression and increases VTA marker expression while having opposite effect to Otx2 ablation; Sox6 deletion also reduces striatal innervation and dopamine levels.","method":"Sox6 conditional knockout, immunohistochemistry, in situ hybridisation, dopamine level measurement, axonal tracing","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multiple molecular and functional readouts; comparison with Otx2 epistasis establishes SNc vs VTA identity role","pmids":["25127144"],"is_preprint":false},{"year":2014,"finding":"Sox2 directly activates Sox6 transcription in neural progenitor cells (Sox6 identified as a direct ChIP-on-chip target of Sox2); Sox6 in turn maintains Sox2 expression, forming a positive feedback loop that inhibits premature neuronal differentiation.","method":"ChIP-on-chip for Sox2, gain- and loss-of-function in neural progenitor cells, in vivo expression analysis in ventricular zone","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-on-chip identifies direct target, functional feedback loop tested by gain/loss of function; single lab","pmids":["24501124"],"is_preprint":false},{"year":2015,"finding":"Trbp (Tarbp2) maintains normal cardiac function in part by promoting miR-208a processing; miR-208a directly inhibits Sox6; loss of Trbp causes impaired miR-208a processing, Sox6 upregulation, and pathological fast-twitch gene expression in the heart; Sox6 knockdown fully rescues the Trbp-mutant cardiomyopathy phenotype, while Sox6 overexpression phenocopies Trbp loss.","method":"Cardiac-specific Trbp conditional KO, Sox6 knockdown rescue, Sox6 transgenic overexpression, miR-208a transgenic rescue, gene expression profiling, cardiac function measurement","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — complete genetic rescue and phenocopy with multiple mouse models; direct miR-208a→Sox6 axis established; replicated by Sox6 overexpression","pmids":["26029872"],"is_preprint":false},{"year":2015,"finding":"SOX6 and SOX9 bind thousands of genomic sites in chondrocytes, frequently co-occupied; SOX9 preferentially recognizes pairs of inverted SOX motifs while SOX6 favors pairs of tandem SOX motifs; both proteins bind multiple sites on nearly all super-enhancers in chondrocytes and are required for in vivo expression of cartilage super-enhancer target genes.","method":"Genome-wide ChIP-seq for SOX6 and SOX9 in RCS cells, motif analysis, super-enhancer analysis, in vivo expression validation","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genome-wide ChIP-seq with motif and super-enhancer analysis, in vivo validation; comprehensive mechanistic study","pmids":["26150426"],"is_preprint":false},{"year":2015,"finding":"Sox5 and Sox6 promote oligodendrocyte progenitor cell migration by maintaining expression of PDGF receptor alpha (a migratory cue receptor); they cooperate with Sox9 and Sox10 to activate Pdgfra expression, keeping cells undifferentiated and migratory; this contrasts with their antagonism of SoxE proteins on myelin genes.","method":"CNS-specific Sox5/Sox6 double conditional knockout mice, gene expression analysis, Pdgf responsiveness assays, immunostaining","journal":"Glia","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional double KO with specific molecular and cellular migration phenotype, mechanistic distinction between target gene contexts","pmids":["26345464"],"is_preprint":false},{"year":2015,"finding":"Sox6 plays opposing roles in MyHC-I regulation depending on developmental stage: during embryonic myogenesis it positively regulates MyHC-I via transcriptional activation of Mef2C, whereas during fetal myogenesis it represses MyHC-I; Nfix is required for Sox6 binding to the MyHC-I promoter and thus for Sox6's repressive function.","method":"ChIP, reporter gene assays, Sox6/Nfix co-expression, gain/loss-of-function in myoblasts, zebrafish nfixa/sox6 conservation analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ChIP showing Nfix requirement for Sox6 promoter binding, reporter assays, stage-specific functional assays; multiple orthogonal methods","pmids":["27880909"],"is_preprint":false},{"year":2015,"finding":"SOX6 suppresses tumor cell proliferation through the p14ARF-HDM2-p53 axis: SOX6 promotes translocation of p14ARF to the nucleoplasm, inhibiting HDM2-mediated p53 nuclear export and degradation; SOX6 also binds the c-Myc gene regulatory region (ChIP) and downregulates c-Myc and its target NPM1, linking NPM1 downregulation to p14ARF nuclear retention; the HMG domain is required for these activities.","method":"Co-immunoprecipitation, immunocytofluorescence, ChIP-PCR, Western blot, cell proliferation assays in vitro and in vivo xenograft","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple assays (Co-IP, immunofluorescence, ChIP, domain mutagenesis), but single lab","pmids":["26119940"],"is_preprint":false},{"year":2010,"finding":"Stat3 directly binds the Sox6 promoter in response to ligand stimulation and is required for Sox6 expression during neuronal differentiation of P19 cells.","method":"ChIP, reporter gene assay, RNAi knockdown, P19 neuronal differentiation model","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding shown by ChIP and reporter assay, RNAi requirement demonstrated; single lab","pmids":["21094641"],"is_preprint":false},{"year":2013,"finding":"MIF upregulates Sox6 expression in neural stem/progenitor cells via Stat3 (ChIP showing increased Stat3 binding at Sox6 promoter); Sox6 overexpression increases neurosphere number, inhibits differentiation, and is accompanied by increased Hes1 and Bcl-2 expression and Akt phosphorylation; Sox6 silencing blocks MIF's ability to increase neurosphere number.","method":"ChIP, retroviral overexpression, siRNA knockdown, neurosphere assays, immunofluorescence, Western blot","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for Stat3 at Sox6 promoter, functional rescue and loss-of-function; single lab","pmids":["24066135"],"is_preprint":false},{"year":2016,"finding":"SOX6 promotes adipogenesis by activating adipogenic regulators PPARγ, C/EBPα, and MEST; SOX6 interacts with β-catenin in adipocytes, suggesting inhibition of WNT/β-catenin signaling; SOX6 binding to the MEST upstream regulatory region is impaired by adjacent CpG methylation.","method":"Adipocyte differentiation from MSCs (umbilical cord), gene expression analysis, co-immunoprecipitation (SOX6-β-catenin), CpG methylation analysis, SOX6 binding assays","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and functional differentiation assays, methylation-binding relationship; single lab, moderate mechanistic depth","pmids":["26893351"],"is_preprint":false},{"year":2019,"finding":"Sox6 is highly expressed in juxtaglomerular (JG) cells of the adult kidney; loss of Sox6 in renin-expressing cells reduces differentiation of renal MSCs to renin-producing cells in vitro and blocks the increase in renin-expressing cells and renin levels in vivo during sodium depletion/furosemide challenge, as well as halting smooth muscle cell recruitment along the afferent arteriole.","method":"Conditional Sox6 knockout in Ren1d+ cells, in vitro differentiation assays, in vivo dietary manipulation (low-Na/furosemide), renin immunostaining, gene expression","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific conditional KO with in vitro and in vivo phenotype; single lab","pmids":["31760770"],"is_preprint":false},{"year":2018,"finding":"Sox6 binds to the Twist1 promoter and represses Twist1 transcription by recruiting HDAC1; Sox6 overexpression inhibits EMT in pancreatic cancer cells and Twist1 overexpression reverses this effect.","method":"ChIP, quantitative ChIP, luciferase reporter assay, co-immunoprecipitation, cell invasion/migration assays, in vivo xenograft, HDAC1 interaction","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct promoter binding, HDAC1 interaction by Co-IP, functional rescue by Twist1 overexpression; single lab","pmids":["29369542"],"is_preprint":false},{"year":2021,"finding":"SOX6 transcriptionally upregulates MAP4K4 by direct binding (via HMG domain) to double-binding sites in the MAP4K4 promoter; MAP4K4 mediates SOX6-induced autophagy through inhibiting PI3K-Akt-mTOR and activating MAPK/ERK pathways, thereby reducing cisplatin chemosensitivity in cervical cancer cells.","method":"ChIP, promoter binding assays, siRNA/overexpression, autophagy assays, PI3K-Akt-mTOR/MAPK signaling analysis, cisplatin sensitivity assays in vitro and in vivo xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct promoter binding, multiple signaling pathway assays; single lab","pmids":["34930918"],"is_preprint":false},{"year":2022,"finding":"Sirt6 deacetylase downregulates Sox6 by increasing CREB transcription; Sirt6 muscle-specific knockout reduces while transgenic overexpression increases mitochondrial oxidative capacity; Sox6 acts downstream of Sirt6-CREB as the key repressor of slow-fiber genes whose suppression shifts muscle toward oxidative fiber type.","method":"Muscle-specific Sirt6 knockout and transgenic mice, gene expression analysis, CREB ChIP/reporter assays, exercise performance assays, Sirt6 activator treatment","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in multiple mouse models (KO and transgenic), ChIP/reporter for CREB→Sox6 axis, pharmacological validation; multiple orthogonal approaches","pmids":["35379817"],"is_preprint":false},{"year":2000,"finding":"Sox6 binds to the leucine zipper region of Solt (a novel testis-specific protein) via Sox6's leucine zipper; co-expression of Solt with Sox6 (fused to VP16 transactivation domain) enhances reporter gene expression driven by Sox binding sites in a Ca2+/calmodulin-dependent protein kinase IV-dependent manner.","method":"Far-Western blot, yeast two-hybrid, in vitro binding assay, transient transfection reporter assay in CHO cells","journal":"FEBS letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid and in vitro binding, reporter assay; functional significance in native context unclear, single lab","pmids":["10996314"],"is_preprint":false},{"year":2020,"finding":"In atopic dermatitis, SOX6 (upregulated when miR-335 is lost) recruits SMARCA complex components to epigenetically suppress epidermal differentiation genes; miR-335 directly represses SOX6 and thereby induces keratinocyte differentiation.","method":"miRNA target validation (luciferase), ChIP for SMARCA complex, keratinocyte differentiation assays, siRNA knockdown, AD patient skin analysis","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for SMARCA complex recruitment, luciferase validation, functional differentiation assays; single lab","pmids":["32088305"],"is_preprint":false},{"year":2024,"finding":"SOX6 induces cellular senescence in cervical cancer via promoting TGFB2 gene expression through MAP4K4-MAPK(JNK/ERK/p38)-ATF2 and WT1-ATF2 pathways, subsequently activating TGFβ2-Smad2/3-p53-p21-Rb signaling; these effects require the HMG domain of SOX6.","method":"Overexpression/knockdown, Western blot, co-immunoprecipitation, ChIP, senescence assays, domain mutagenesis (HMG), in vitro and in vivo xenograft","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and Co-IP with domain mutagenesis, multiple pathway readouts; single lab","pmids":["38383842"],"is_preprint":false}],"current_model":"SOX6 is an SRY-related HMG-box transcription factor that functions primarily as a transcriptional repressor (and context-dependent activator) by binding pairs of HMG recognition sites, often as a homodimer or L-Sox5 heterodimer via its coiled-coil domain; it recruits co-repressors (CtBP2, HDAC1) to silence targets (Fgf-3, gamma/epsilon-globin, MyHC-beta, cyclin D1, Twist1), cooperates with Sox9 by stabilizing its chromatin occupancy on cartilage super-enhancers (Col2a1, Agc1, miR-140) to drive chondrogenesis, interacts with BCL11A and GATA1 to silence fetal globin in erythropoiesis, promotes erythroid cell survival partly by upregulating Bcl2l1/Bcl-xL and SOCS3, specifies SNc dopamine neuron identity, represses slow-fiber genes in fast-twitch skeletal muscle (regulated in turn by Prdm1/miR-499 and Sirt6-CREB), co-represses PDX1-driven insulin gene expression, is itself negatively autoregulated via a double HMG binding site in its own promoter, and is post-translationally repressed by SUMOylation at two sites that promote its relocalization to PML bodies."},"narrative":{"mechanistic_narrative":"SOX6 is an SRY-related HMG-box transcription factor that orchestrates cell-type specification and differentiation across cartilage, blood, muscle, and the nervous system by binding paired HMG recognition sites, acting predominantly as a transcriptional repressor but also as a context-dependent activator [PMID:9755172, PMID:21985497]. Its coiled-coil domain mediates homodimerization and heterodimerization with L-Sox5, which markedly enhances DNA binding to adjacent HMG sites [PMID:9755172]. In chondrogenesis, SOX6 acts downstream of Sox9 [PMID:12414734] and, together with L-Sox5, secures and potentiates Sox9 occupancy on cartilage super-enhancers driving Col2a1, aggrecan (Agc1), and miR-140 expression [PMID:18559420, PMID:22547066]; genome-wide, SOX6 and SOX9 co-occupy thousands of chondrocyte sites with distinct motif preferences (tandem versus inverted SOX motifs) and are required for super-enhancer target expression [PMID:26150426]. SOX5/SOX6 are also required cell-autonomously for notochord matrix sheath formation and nucleus pulposus development [PMID:12571105]. As a repressor, SOX6 recruits co-repressors: CtBP2 via an N-terminal PLNLSS motif to silence Fgf-3 [PMID:11504872], and HDAC1 to repress Twist1 and reduce promoter histone acetylation [PMID:29369542]. In erythropoiesis SOX6 silences embryonic/fetal globin genes—directly binding the epsilon-globin promoter [PMID:16462943] and physically partnering with BCL11A and GATA1 to silence gamma-globin and reorganize the beta-globin locus [PMID:20395365]—while promoting erythroblast survival and maturation by directly upregulating Bcl2l1/Bcl-xL [PMID:16627753, PMID:20711497] and SOCS3 [PMID:21263153]. In skeletal muscle SOX6 is a direct repressor of slow-fiber sarcomere and developmental genes, its genomic targets being predominantly transcriptionally inactive [PMID:21985497, PMID:17584907], a function whose loss in the heart drives pathological fast-twitch gene expression [PMID:26029872]; SOX6 levels are themselves controlled by upstream Prdm1/miR-499 and Sirt6-CREB circuits [PMID:18535625, PMID:21880783, PMID:35379817]. In the nervous system SOX6 specifies substantia nigra dopamine neuron identity [PMID:25127144], drives maturation of MGE-derived cortical interneurons downstream of Lhx6 [PMID:19709629], and segregates pallial from subpallial telencephalic progenitor identity [PMID:19657336]. SOX6 activity is restrained by negative autoregulation through a double HMG site in its own promoter [PMID:20852263] and by SUMOylation at two sites that relocalize it to PML bodies [PMID:16442531]. SOX6 missense-disrupting interactions with SHOX, mutated in Léri-Weill dyschondrosteosis/idiopathic short stature, impair Agc1 enhancer activation, linking the SOX6-SHOX axis to skeletal growth disease [PMID:21262861].","teleology":[{"year":1998,"claim":"Established the biochemical basis of SOX6 function—how it achieves efficient, site-specific DNA binding and cooperates in transcriptional activation.","evidence":"Dimerization and EMSA assays plus transgenic enhancer analysis of the Col2a1 chondrocyte element in cell lines and mice","pmids":["9755172"],"confidence":"High","gaps":["Did not resolve whether dimerization underlies repression as well as activation","Structure of the HMG-DNA complex not determined"]},{"year":2001,"claim":"Defined a molecular mechanism for SOX6-mediated repression by identifying a co-repressor recruitment motif.","evidence":"Yeast one/two-hybrid, mutagenesis of the PLNLSS motif, and Fgf-3 reporter assays in NIH3T3 cells","pmids":["11504872"],"confidence":"High","gaps":["Generality of CtBP2 use across other SOX6 targets not tested","In vivo requirement of the motif not assessed"]},{"year":2002,"claim":"Placed SOX6 within the chondrogenic transcription factor hierarchy by showing Sox9 acts upstream of its expression.","evidence":"Cre/loxP conditional Sox9 knockout with genetic epistasis in mouse","pmids":["12414734"],"confidence":"High","gaps":["Direct regulation of the Sox6 gene by Sox9 not shown","Mechanism of Sox9-dependent induction unresolved"]},{"year":2003,"claim":"Demonstrated essential cell-autonomous SOX5/SOX6 roles in notochord matrix and intervertebral disc development.","evidence":"Sox5/Sox6 double-null mouse analysis with marker in situ hybridisation and immunohistochemistry","pmids":["12571105","14530442"],"confidence":"High","gaps":["Direct target genes in notochord not mapped","Cardiomyocyte Prtb interaction (idx 4) of uncertain general significance"]},{"year":2005,"claim":"Extended SOX6 to metabolic gene control, showing it co-represses insulin transcription via PDX1.","evidence":"Domain-mapped binding, ChIP, histone acetylation and secretion assays in MIN6/INS-1E cells","pmids":["16148004"],"confidence":"High","gaps":["In vivo relevance to pancreatic beta-cell function not established","Co-repressor identity at the insulin promoter not defined"]},{"year":2006,"claim":"Established SOX6 as a direct globin repressor and survival factor in erythropoiesis, defining dual transcriptional and pro-survival roles.","evidence":"EMSA, ChIP, reporter assays and Sox6-deficient and erythroid-specific conditional knockout mice","pmids":["16462943","16627753"],"confidence":"High","gaps":["Co-repressor complex at globin promoters not defined in these studies","Mechanism linking SOX6 to F-actin stability unresolved"]},{"year":2006,"claim":"Identified SUMOylation as a post-translational switch restraining SOX6 activity and relocalizing it to PML bodies.","evidence":"In vitro/in vivo SUMOylation, acceptor-lysine mutagenesis, UBC9 manipulation and immunofluorescence","pmids":["16442531"],"confidence":"High","gaps":["Physiological signals triggering SOX6 SUMOylation unknown","Functional consequence of PML relocalization on specific targets untested"]},{"year":2007,"claim":"Linked SOX6 to cell-cycle and proliferation control through beta-catenin/HDAC1-dependent cyclin D1 repression, and defined its slow-fiber repressor role in muscle.","evidence":"GST pulldown, ChIP, proliferation assays; Sox6 null mice and MyHC-beta promoter analysis","pmids":["17412698","17584907"],"confidence":"High","gaps":["Whether cyclin D1 repression operates in vivo not shown","Genome-wide muscle target scope not yet defined at this stage"]},{"year":2008,"claim":"Resolved the chondrogenic cooperativity mechanism—L-Sox5/Sox6 enhance Sox9 binding at cartilage enhancers—and identified upstream Prdm1 repression of sox6 in muscle.","evidence":"Transgenic enhancer assays, ChIP, EMSA on Agc1/Col2a1; ChIP and ubo mutant epistasis in zebrafish","pmids":["18559420","18535625"],"confidence":"High","gaps":["Structural basis of Sox5/6-enhanced Sox9 occupancy unknown","Whether Prdm1 repression of sox6 is conserved in mammals not addressed here"]},{"year":2009,"claim":"Established SOX6 as a key regulator of neuronal identity and maturation across interneuron and telencephalic progenitor lineages, and reported an antagonistic splicing-related interaction with DAX-1.","evidence":"Sox6 null and conditional knockout mice with electrophysiology and Lhx6 epistasis; yeast two-hybrid and in vitro splicing assays","pmids":["19709629","19657336","19384854"],"confidence":"High","gaps":["Direct neuronal target genes of SOX6 not mapped","DAX-1/splicing role (idx 15, Medium) lacks in vivo confirmation"]},{"year":2010,"claim":"Defined the SOX6 erythroid regulatory network—BCL11A/GATA1 partnership at the beta-globin locus, direct Bcl2l1 activation, and negative autoregulation—and identified Stat3 as an upstream activator.","evidence":"ChIP-chip, 3C, Co-IP, conditional KO, EMSA, autoregulatory site analysis; Stat3 ChIP/reporter in P19 cells","pmids":["20395365","20711497","20852263","21094641"],"confidence":"High","gaps":["Bcl2l1 regulation (idx 17, Medium) lacks direct ChIP in that study","Stat3-Sox6 link (idx 31, Medium) shown in single cell model"]},{"year":2011,"claim":"Provided genome-wide proof that SOX6 acts as a direct transcriptional suppressor in muscle, defined a Prdm1a/miR-499 lineage loop, and linked SHOX disease mutations to the SOX6 chondrogenic complex.","evidence":"Sox6/Pol II ChIP-seq with muscle-specific KO; zebrafish cis-regulatory and miR-499 analysis; SHOX Co-IP, domain mapping and patient mutation reporter assays","pmids":["21985497","21880783","21262861","21263153"],"confidence":"High","gaps":["Co-repressor machinery driving genome-wide muscle suppression not resolved","SOCS3 activation (idx 19) tested mainly in overexpression contexts"]},{"year":2012,"claim":"Extended chondrogenic cooperativity to a microRNA target, showing L-Sox5/Sox6 potentiate Sox9 activation of miR-140.","evidence":"Transgenic reporter, ChIP and binding-site mutagenesis of the pri-miR-140 promoter","pmids":["22547066"],"confidence":"High","gaps":["Whether miR-140 mediates downstream SOX6 chondrogenic effects not addressed","Quantitative contribution of SOX6 versus SOX9 not separated"]},{"year":2014,"claim":"Established SOX6 as a specifier of substantia nigra dopamine neuron identity and revealed a Sox2-Sox6 feedback loop controlling neural progenitor differentiation timing.","evidence":"Conditional KO with Otx2 epistasis and dopamine measurement; Sox2 ChIP-on-chip with gain/loss-of-function","pmids":["25127144","24501124"],"confidence":"High","gaps":["Direct SOX6 targets defining SNc identity not identified","Sox2-Sox6 loop (idx 25, Medium) characterized in one system"]},{"year":2015,"claim":"Broadened SOX6's regulatory logic—stage-dependent and partner-dependent (Nfix) muscle control, oligodendrocyte migration via Pdgfra, a cardiac Trbp/miR-208a→Sox6 disease axis, genome-wide chondrocyte super-enhancer co-occupancy with SOX9, and a tumor-suppressive p14ARF-p53 mechanism.","evidence":"ChIP/reporter with Nfix; double conditional KO; Trbp KO with Sox6 rescue/phenocopy mice; SOX6/SOX9 ChIP-seq and super-enhancer analysis; Co-IP, ChIP and xenografts","pmids":["27880909","26345464","26029872","26150426","26119940"],"confidence":"High","gaps":["Mechanism switching SOX6 between activator and repressor states incompletely defined","p14ARF-p53 tumor mechanism (idx 30, Medium) from single lab"]},{"year":2022,"claim":"Integrated SOX6 into broader physiological and disease circuits—adipogenesis, juxtaglomerular renin cell differentiation, atopic dermatitis epidermal control, cancer senescence/autophagy, and the Sirt6-CREB-Sox6 oxidative muscle axis.","evidence":"Differentiation assays, conditional KO, ChIP for SMARCA/CREB, signaling and senescence assays, multiple mouse models","pmids":["26893351","31760770","32088305","34930918","38383842","35379817"],"confidence":"Medium","gaps":["Several disease mechanisms (adipogenesis, AD, cancer pathways) rest on single-lab studies","Direct chromatin targets in non-canonical tissues not comprehensively mapped"]},{"year":null,"claim":"How SOX6 is switched between transcriptional repressor and activator states, and what co-factor and chromatin context determines target selectivity genome-wide, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural or biochemical model for activator-versus-repressor switching","Full co-repressor/co-activator complex composition at most targets undefined","Role of SUMOylation and PML relocalization in target-specific regulation in vivo untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,6,10,20,27]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,6,18,20,27]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[11,23,5,9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,20,27]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[8,30]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,6,20,27]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,3,13,14,24,28]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[5,9,16,35,39]}],"complexes":[],"partners":["SOX5","SOX9","CTBP2","HDAC1","BCL11A","GATA1","CTNNB1","PDX1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P35712","full_name":"Transcription factor SOX-6","aliases":[],"length_aa":828,"mass_kda":91.9,"function":"Transcription factor that plays a key role in several developmental processes, including neurogenesis, chondrocytes differentiation and cartilage formation (Probable). Specifically binds the 5'-AACAAT-3' DNA motif present in enhancers and super-enhancers and promotes expression of genes important for chondrogenesis. Required for overt chondrogenesis when condensed prechondrocytes differentiate into early stage chondrocytes: SOX5 and SOX6 cooperatively bind with SOX9 on active enhancers and super-enhancers associated with cartilage-specific genes, and thereby potentiate SOX9's ability to transactivate. Not involved in precartilaginous condensation, the first step in chondrogenesis, during which skeletal progenitors differentiate into prechondrocytes. Together with SOX5, required to form and maintain a pool of highly proliferating chondroblasts between epiphyses and metaphyses, to form columnar chondroblasts, delay chondrocyte prehypertrophy but promote hypertrophy, and to delay terminal differentiation of chondrocytes on contact with ossification fronts. Binds to the proximal promoter region of the myelin protein MPZ gene, and is thereby involved in the differentiation of oligodendroglia in the developing spinal tube. Binds to the gene promoter of MBP and acts as a transcriptional repressor (By similarity)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P35712/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SOX6","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":[],"url":"https://opencell.sf.czbiohub.org/search/SOX6","total_profiled":1310},"omim":[{"mim_id":"620969","title":"ANEMIA, CONGENITAL DYSERYTHROPOIETIC, TYPE IVb; CDAN4B","url":"https://www.omim.org/entry/620969"},{"mim_id":"618971","title":"TOLCHIN-LE CAIGNEC SYNDROME; TOLCAS","url":"https://www.omim.org/entry/618971"},{"mim_id":"614206","title":"CHROMATIN TARGET OF PRMT1; CHTOP","url":"https://www.omim.org/entry/614206"},{"mim_id":"614059","title":"MICRO RNA 338; MIR338","url":"https://www.omim.org/entry/614059"},{"mim_id":"613902","title":"ZINC FINGER PROTEIN 503; ZNF503","url":"https://www.omim.org/entry/613902"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":25.3}],"url":"https://www.proteinatlas.org/search/SOX6"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P35712","domains":[{"cath_id":"1.10.30.10","chopping":"628-692","consensus_level":"high","plddt":96.3586,"start":628,"end":692},{"cath_id":"1.20.5","chopping":"131-162","consensus_level":"medium","plddt":66.7228,"start":131,"end":162},{"cath_id":"1.20.5","chopping":"187-259","consensus_level":"medium","plddt":93.0718,"start":187,"end":259},{"cath_id":"1.20.5","chopping":"693-726","consensus_level":"medium","plddt":83.5994,"start":693,"end":726}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P35712","model_url":"https://alphafold.ebi.ac.uk/files/AF-P35712-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P35712-F1-predicted_aligned_error_v6.png","plddt_mean":55.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SOX6","jax_strain_url":"https://www.jax.org/strain/search?query=SOX6"},"sequence":{"accession":"P35712","fasta_url":"https://rest.uniprot.org/uniprotkb/P35712.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P35712/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P35712"}},"corpus_meta":[{"pmid":"12414734","id":"PMC_12414734","title":"The 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L-Sox5, Sox6, and Sox9 cooperatively activate the Col2a1 chondrocyte-specific enhancer by directly binding to HMG-like sites within a 48 bp element.\",\n      \"method\": \"Protein dimerization assays, DNA binding/EMSA, reporter gene (luciferase) assays in 10T1/2 and MC615 cells, transgenic mouse enhancer analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro binding, dimerization assays, and in vivo transgenic validation in single rigorous study; replicated by multiple subsequent papers\",\n      \"pmids\": [\"9755172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Sox6 represses transcription from the Fgf-3 promoter through the PS4A regulatory element, and recruits the co-repressor CtBP2 via a short PLNLSS motif in its N-terminal region; mutation of this motif abolishes CtBP2 binding and CtBP2-dependent repression.\",\n      \"method\": \"Yeast one-hybrid screen, yeast two-hybrid screen, reporter gene assays in NIH3T3 cells, site-directed mutagenesis, co-expression studies, in situ hybridisation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — yeast two-hybrid confirmed in mammalian cells, mutagenesis of binding motif, reporter assay; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"11504872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Sox9 is required upstream of Sox5 and Sox6 for their expression in chondrogenic mesenchymal cells; conditional Sox9 inactivation before mesenchymal condensations abolishes Sox5 and Sox6 expression, placing Sox9 upstream in the chondrogenic transcription factor hierarchy.\",\n      \"method\": \"Cre/loxP conditional knockout mice, in situ hybridisation, immunohistochemistry, genetic epistasis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic epistasis in mouse, replicated across developmental stages, widely cited\",\n      \"pmids\": [\"12414734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Sox5 and Sox6 are required cell-autonomously for notochord extracellular matrix sheath formation (including Col2a1, aggrecan, perlecan expression), notochord cell survival, and nucleus pulposus development in intervertebral discs; double knockout mice lack nuclei pulposi and show progressive notochord apoptosis.\",\n      \"method\": \"Sox5/Sox6 double-null mouse genetic analysis, in situ hybridisation, immunohistochemistry, gene expression analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean double KO with specific molecular and cellular phenotype, multiple markers, in vivo\",\n      \"pmids\": [\"12571105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Sox6 is expressed exclusively during cardiomyocyte commitment in P19CL6 cells, interacts physically with Prtb (Proline-rich transcript of the brain) protein, and represses expression of the L-type Ca2+ channel alpha1c subunit; BMP signaling is required upstream for Sox6 expression in this context.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, P19CL6 cardiomyocyte differentiation model, noggin-expressing stable cells, in vivo comparison of WT vs p100H mutant mice\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — yeast two-hybrid confirmed by Co-IP, functional readout in cell model and in vivo, single lab\",\n      \"pmids\": [\"14530442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SOX6 acts as a co-repressor of PDX1-mediated insulin gene transcription through a direct protein-protein interaction between the LZ/Q domain of SOX6 and PDX1; SOX6 overexpression reduces histone H3/H4 acetylation at the insulin II promoter, suppressing glucose-stimulated insulin secretion.\",\n      \"method\": \"siRNA knockdown, retroviral overexpression, luciferase reporter assay, in vitro binding, chromatin immunoprecipitation (ChIP), ATP/ADP ratio, Ca2+ mobilization assays in MIN6 and INS-1E cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct protein interaction mapped to domains, ChIP, functional metabolic readouts, multiple orthogonal methods in single study\",\n      \"pmids\": [\"16148004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Sox6 directly binds the epsilony-globin proximal promoter (36 bp region) in definitive erythropoiesis and acts as a transcriptional repressor to silence epsilon-globin; loss of Sox6 in p100H mice results in persistent epsilony expression in fetal liver definitive erythrocytes.\",\n      \"method\": \"EMSA, ChIP, transfection reporter assays in GM979 cells, Sox6-deficient mouse analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct DNA binding shown by EMSA and ChIP, functional repression confirmed in cell and mouse models\",\n      \"pmids\": [\"16462943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Sox6 cell-autonomously promotes proerythroblast survival and proliferation, facilitates erythroblast maturation (hemoglobinization, condensation, enucleation), and stabilizes F-actin levels in erythroid cells; erythroid-specific inactivation phenocopies germline null, demonstrating cell-autonomous roles.\",\n      \"method\": \"Erythroid-specific conditional Sox6 knockout (Sox6fl/fl x ErGFPCre), flow cytometry, in vitro EPO signaling assays, F-actin staining, bone marrow and fetal liver analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO with defined molecular (F-actin) and cellular phenotypes; multiple orthogonal assays\",\n      \"pmids\": [\"16627753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SOX6 transcriptional activity is repressed by SUMO modification at two distinct sites; mutation of both SUMO sites increases SOX6 transcriptional activity; UBC9 promotes SUMO-dependent repression and SUMO protease/siRNA to UBC9 increases activity; SUMO2 co-expression relocalizes SOX6 to punctate nuclear foci colocalizing with PML bodies.\",\n      \"method\": \"In vitro and in vivo SUMOylation assays, site-directed mutagenesis of SUMO acceptor lysines, reporter gene assays, siRNA, immunofluorescence microscopy\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro and in vivo PTM demonstrated, mutagenesis abolishes modification and shows functional consequence, subcellular localization change documented\",\n      \"pmids\": [\"16442531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SOX6 suppresses cyclin D1 promoter activity by physically interacting with beta-catenin (via LZ/Q domain binding to armadillo repeats 1-4) and HDAC1; SOX6 overexpression reduces acetylated histones H3 and H4 at the cyclin D1 promoter, inhibiting cell proliferation; SOX6 knockdown stimulates INS-1E and NIH-3T3 cell proliferation.\",\n      \"method\": \"siRNA, retroviral overexpression, luciferase reporter assay, in vitro binding (GST pulldown), ChIP, HDAC inhibitor, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — domain-mapped protein interaction, ChIP confirming chromatin changes, functional proliferation assays; multiple orthogonal methods single lab\",\n      \"pmids\": [\"17412698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Sox6 functions as a transcriptional repressor of slow fiber-type specific genes (including MyHC-beta/MyHC-I) in fetal skeletal muscle; Sox6 null mice have all fetal fibers maintaining slow characteristics; a Sox consensus sequence in the MyHC-beta promoter functions as a negative cis-regulatory element bound by Sox6.\",\n      \"method\": \"Sox6 null mouse phenotype analysis, siRNA knockdown in myotubes, MyHC-beta promoter analysis, reporter assays\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo null phenotype with molecular promoter analysis and siRNA confirmation; multiple approaches\",\n      \"pmids\": [\"17584907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"L-Sox5/Sox6 enhances Sox9 binding to its recognition site on the Agc1 (aggrecan) far-upstream enhancer by binding to three additional flanking elements, thereby potentiating Sox9 transcriptional activation; L-Sox5/Sox6 similarly secures Sox9 binding at Col2a1 and other cartilage-specific enhancers.\",\n      \"method\": \"Transgenic mouse enhancer assays, ChIP, EMSA, reporter gene assays, site-directed mutagenesis of cis-elements\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mechanistic ChIP, EMSA, mutagenesis and transgenic validation; multiple orthogonal methods\",\n      \"pmids\": [\"18559420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Prdm1 promotes slow-twitch muscle fiber differentiation in zebrafish by acting as a transcriptional repressor that directly represses sox6 (shown by ChIP); Prdm1-mediated repression of Sox6 relieves Sox6's repression of slow-fiber-specific genes, thereby enabling slow-twitch gene expression in adaxial cells.\",\n      \"method\": \"ChIP in zebrafish embryos, ubo mutant analysis, gene expression assays, epistasis\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct ChIP evidence for Prdm1 occupancy at sox6 targets, clear epistatic rescue, zebrafish ortholog\",\n      \"pmids\": [\"18535625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Sox6 functions downstream of Lhx6 in MGE-derived cortical interneuron development; Sox6 null animals phenocopy Lhx6 null animals with loss of PV and SST expression and mispositioned basket/Martinotti neurons; basket cells in Sox6 mutants retain immature fast-spiking features, indicating Sox6 is required for maturation but not specification.\",\n      \"method\": \"Sox6 null mouse analysis, electrophysiology, genetic epistasis with Lhx6 null, immunostaining, position analysis\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — null mouse with electrophysiology, epistasis with Lhx6, specific cellular phenotype with molecular markers\",\n      \"pmids\": [\"19709629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SOX6 controls molecular segregation of dorsal (pallial) from ventral (subpallial) telencephalic progenitors; loss of SOX6 from pallial progenitors causes inappropriate expression of subpallium-restricted developmental controls; SOX6 and SOX5 are mutually exclusively expressed in pallial/subpallial progenitors and in reverse pattern in postmitotic neurons.\",\n      \"method\": \"Sox6 conditional knockout mice, immunohistochemistry, in situ hybridisation, gene expression profiling\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with specific molecular and cellular phenotype, comparison with Sox5 pattern\",\n      \"pmids\": [\"19657336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DAX-1 and SOX6 interact physically (confirmed by yeast two-hybrid and biochemical assays) and act antagonistically in pre-mRNA splicing: DAX-1 inhibits splicing in vivo and in vitro, and SOX6 relieves this inhibition by interfering with the DAX-1/splicing machinery interaction.\",\n      \"method\": \"Yeast two-hybrid, biochemical co-precipitation, in vivo and in vitro splicing assays\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed biochemically, in vitro splicing assay with mechanistic model; single lab\",\n      \"pmids\": [\"19384854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"BCL11A and SOX6 physically interact and co-occupy the human beta-globin cluster along with GATA1, cooperating to silence gamma-globin transcription in adult human erythroid progenitors; BCL11A modulates chromosomal loop formation at the beta-globin locus.\",\n      \"method\": \"ChIP-chip, chromosome conformation capture (3C), co-immunoprecipitation, siRNA knockdown in adult erythroid progenitors\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — physical interaction by Co-IP, chromatin occupancy by ChIP-chip, loop formation by 3C, functional knockdown; multiple orthogonal methods\",\n      \"pmids\": [\"20395365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Sox6 directly upregulates Bcl2l1 (encoding anti-apoptotic Bcl-xL) in erythroid cells downstream of erythropoietin signaling; conditional Sox6 inactivation in adult mice causes downregulation of Bcl2l1 and in vitro assays confirm Sox6 direct regulation of this gene.\",\n      \"method\": \"Conditional Sox6 knockout (Sox6fl/flCaggCreER and Sox6fl/flErGFPCre), tamoxifen induction, gene expression profiling, in vitro erythroblast assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with target gene readout and in vitro confirmation; single lab, molecular target validated but not by direct ChIP in this paper\",\n      \"pmids\": [\"20711497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A highly conserved double Sox6 binding site within the Sox6 gene promoter mediates negative autoregulation: Sox6 protein binds this site in vitro and in vivo (ChIP), reduces chromatin accessibility, and transcriptionally represses its own gene in erythroid cells.\",\n      \"method\": \"Bioinformatic genome-wide search, EMSA, ChIP, luciferase reporter assays in K562 and primary erythroblasts, chromatin accessibility (PstI restriction), lentiviral transduction\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro and in vivo binding, ChIP, reporter assays, functional readout; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"20852263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Sox6 overexpression in human erythroid progenitors (K562 and cord blood CD34+ cells) enhances erythroid differentiation and directly activates SOCS3 expression by binding to a conserved regulatory element in the SOCS3 gene; SOCS3 overexpression recapitulates Sox6-induced growth inhibition.\",\n      \"method\": \"Lentiviral overexpression in K562 and primary human erythroid cultures, EMSA, ChIP, reporter assays, SOCS3 rescue experiment\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct binding of Sox6 to SOCS3 regulatory element by EMSA and ChIP, functional rescue with SOCS3 overexpression; multiple orthogonal methods\",\n      \"pmids\": [\"21263153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In mouse fetal myotubes, Sox6 genome-wide binding (ChIP-seq) is predominantly associated with slow fiber-specific, cardiac, and embryonic isoform sarcomere genes as well as muscle developmental transcription factor genes; RNA Pol II ChIP-seq shows 84% of Sox6-bound genes are transcriptionally inactive, confirming Sox6 acts as a direct transcriptional suppressor; muscle-specific Sox6 KO adult mice show dramatic upregulation of these bound genes.\",\n      \"method\": \"ChIP-seq (Sox6 and RNA Pol II), muscle-specific Sox6 knockout mice, gene expression profiling\",\n      \"journal\": \"BMC developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genome-wide ChIP-seq with matched RNA Pol II occupancy plus conditional KO; multiple orthogonal methods confirming direct repressor role\",\n      \"pmids\": [\"21985497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SHOX interacts physically with SOX6 (and SOX5) via the SHOX homeodomain and SOX6 HMG domain; SHOX cooperates with SOX5/SOX6 and SOX9 to activate the upstream Agc1 enhancer; LWD/ISS patient SHOX missense mutations disrupt this interaction and impair Agc1 activation.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in human cells, immunohistochemistry on human fetal growth plate, domain mutagenesis, luciferase reporter assays\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — reciprocal Co-IP, domain mapping, patient mutation disruption, reporter assay; multiple orthogonal methods single lab\",\n      \"pmids\": [\"21262861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Sox6 transcription in zebrafish slow-twitch progenitors is repressed by Prdm1a transcriptionally; subsequently, miR-499 (whose expression is controlled by Prdm1a) restricts Sox6 protein to fast-twitch fibers by translational repression, forming a regulatory loop that maintains the slow-twitch lineage.\",\n      \"method\": \"Cis-regulatory reporter transgenics, morpholino knockdown, miR-499 analysis, Prdm1a-dependent expression assays in zebrafish\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cis-regulatory elements characterised in transgenic fish, Prdm1a-dependence shown, miR-499 translational repression demonstrated; multiple orthogonal methods\",\n      \"pmids\": [\"21880783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"L-Sox5 and Sox6 enhance Sox9 homodimer-mediated transcriptional activation of miR-140, a cartilage-specific microRNA; a Sox trio response element and detailed binding site were mapped in the pri-miR-140 promoter; L-Sox5/Sox6 boost Sox9 DNA binding and/or transactivation as a homodimer.\",\n      \"method\": \"Transgenic mouse reporter assays, ChIP, reporter gene assays in chondrocyte cell lines, binding site mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vivo transgenic reporter, ChIP, detailed mutagenesis of binding site; multiple methods single lab\",\n      \"pmids\": [\"22547066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Sox6 selectively marks and specifies substantia nigra (SNc) dopamine neurons; Sox6 ablation decreases SNc marker expression and increases VTA marker expression while having opposite effect to Otx2 ablation; Sox6 deletion also reduces striatal innervation and dopamine levels.\",\n      \"method\": \"Sox6 conditional knockout, immunohistochemistry, in situ hybridisation, dopamine level measurement, axonal tracing\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multiple molecular and functional readouts; comparison with Otx2 epistasis establishes SNc vs VTA identity role\",\n      \"pmids\": [\"25127144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Sox2 directly activates Sox6 transcription in neural progenitor cells (Sox6 identified as a direct ChIP-on-chip target of Sox2); Sox6 in turn maintains Sox2 expression, forming a positive feedback loop that inhibits premature neuronal differentiation.\",\n      \"method\": \"ChIP-on-chip for Sox2, gain- and loss-of-function in neural progenitor cells, in vivo expression analysis in ventricular zone\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-on-chip identifies direct target, functional feedback loop tested by gain/loss of function; single lab\",\n      \"pmids\": [\"24501124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Trbp (Tarbp2) maintains normal cardiac function in part by promoting miR-208a processing; miR-208a directly inhibits Sox6; loss of Trbp causes impaired miR-208a processing, Sox6 upregulation, and pathological fast-twitch gene expression in the heart; Sox6 knockdown fully rescues the Trbp-mutant cardiomyopathy phenotype, while Sox6 overexpression phenocopies Trbp loss.\",\n      \"method\": \"Cardiac-specific Trbp conditional KO, Sox6 knockdown rescue, Sox6 transgenic overexpression, miR-208a transgenic rescue, gene expression profiling, cardiac function measurement\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — complete genetic rescue and phenocopy with multiple mouse models; direct miR-208a→Sox6 axis established; replicated by Sox6 overexpression\",\n      \"pmids\": [\"26029872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SOX6 and SOX9 bind thousands of genomic sites in chondrocytes, frequently co-occupied; SOX9 preferentially recognizes pairs of inverted SOX motifs while SOX6 favors pairs of tandem SOX motifs; both proteins bind multiple sites on nearly all super-enhancers in chondrocytes and are required for in vivo expression of cartilage super-enhancer target genes.\",\n      \"method\": \"Genome-wide ChIP-seq for SOX6 and SOX9 in RCS cells, motif analysis, super-enhancer analysis, in vivo expression validation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genome-wide ChIP-seq with motif and super-enhancer analysis, in vivo validation; comprehensive mechanistic study\",\n      \"pmids\": [\"26150426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Sox5 and Sox6 promote oligodendrocyte progenitor cell migration by maintaining expression of PDGF receptor alpha (a migratory cue receptor); they cooperate with Sox9 and Sox10 to activate Pdgfra expression, keeping cells undifferentiated and migratory; this contrasts with their antagonism of SoxE proteins on myelin genes.\",\n      \"method\": \"CNS-specific Sox5/Sox6 double conditional knockout mice, gene expression analysis, Pdgf responsiveness assays, immunostaining\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional double KO with specific molecular and cellular migration phenotype, mechanistic distinction between target gene contexts\",\n      \"pmids\": [\"26345464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Sox6 plays opposing roles in MyHC-I regulation depending on developmental stage: during embryonic myogenesis it positively regulates MyHC-I via transcriptional activation of Mef2C, whereas during fetal myogenesis it represses MyHC-I; Nfix is required for Sox6 binding to the MyHC-I promoter and thus for Sox6's repressive function.\",\n      \"method\": \"ChIP, reporter gene assays, Sox6/Nfix co-expression, gain/loss-of-function in myoblasts, zebrafish nfixa/sox6 conservation analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP showing Nfix requirement for Sox6 promoter binding, reporter assays, stage-specific functional assays; multiple orthogonal methods\",\n      \"pmids\": [\"27880909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SOX6 suppresses tumor cell proliferation through the p14ARF-HDM2-p53 axis: SOX6 promotes translocation of p14ARF to the nucleoplasm, inhibiting HDM2-mediated p53 nuclear export and degradation; SOX6 also binds the c-Myc gene regulatory region (ChIP) and downregulates c-Myc and its target NPM1, linking NPM1 downregulation to p14ARF nuclear retention; the HMG domain is required for these activities.\",\n      \"method\": \"Co-immunoprecipitation, immunocytofluorescence, ChIP-PCR, Western blot, cell proliferation assays in vitro and in vivo xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple assays (Co-IP, immunofluorescence, ChIP, domain mutagenesis), but single lab\",\n      \"pmids\": [\"26119940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Stat3 directly binds the Sox6 promoter in response to ligand stimulation and is required for Sox6 expression during neuronal differentiation of P19 cells.\",\n      \"method\": \"ChIP, reporter gene assay, RNAi knockdown, P19 neuronal differentiation model\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding shown by ChIP and reporter assay, RNAi requirement demonstrated; single lab\",\n      \"pmids\": [\"21094641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MIF upregulates Sox6 expression in neural stem/progenitor cells via Stat3 (ChIP showing increased Stat3 binding at Sox6 promoter); Sox6 overexpression increases neurosphere number, inhibits differentiation, and is accompanied by increased Hes1 and Bcl-2 expression and Akt phosphorylation; Sox6 silencing blocks MIF's ability to increase neurosphere number.\",\n      \"method\": \"ChIP, retroviral overexpression, siRNA knockdown, neurosphere assays, immunofluorescence, Western blot\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for Stat3 at Sox6 promoter, functional rescue and loss-of-function; single lab\",\n      \"pmids\": [\"24066135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SOX6 promotes adipogenesis by activating adipogenic regulators PPARγ, C/EBPα, and MEST; SOX6 interacts with β-catenin in adipocytes, suggesting inhibition of WNT/β-catenin signaling; SOX6 binding to the MEST upstream regulatory region is impaired by adjacent CpG methylation.\",\n      \"method\": \"Adipocyte differentiation from MSCs (umbilical cord), gene expression analysis, co-immunoprecipitation (SOX6-β-catenin), CpG methylation analysis, SOX6 binding assays\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and functional differentiation assays, methylation-binding relationship; single lab, moderate mechanistic depth\",\n      \"pmids\": [\"26893351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Sox6 is highly expressed in juxtaglomerular (JG) cells of the adult kidney; loss of Sox6 in renin-expressing cells reduces differentiation of renal MSCs to renin-producing cells in vitro and blocks the increase in renin-expressing cells and renin levels in vivo during sodium depletion/furosemide challenge, as well as halting smooth muscle cell recruitment along the afferent arteriole.\",\n      \"method\": \"Conditional Sox6 knockout in Ren1d+ cells, in vitro differentiation assays, in vivo dietary manipulation (low-Na/furosemide), renin immunostaining, gene expression\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific conditional KO with in vitro and in vivo phenotype; single lab\",\n      \"pmids\": [\"31760770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Sox6 binds to the Twist1 promoter and represses Twist1 transcription by recruiting HDAC1; Sox6 overexpression inhibits EMT in pancreatic cancer cells and Twist1 overexpression reverses this effect.\",\n      \"method\": \"ChIP, quantitative ChIP, luciferase reporter assay, co-immunoprecipitation, cell invasion/migration assays, in vivo xenograft, HDAC1 interaction\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct promoter binding, HDAC1 interaction by Co-IP, functional rescue by Twist1 overexpression; single lab\",\n      \"pmids\": [\"29369542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SOX6 transcriptionally upregulates MAP4K4 by direct binding (via HMG domain) to double-binding sites in the MAP4K4 promoter; MAP4K4 mediates SOX6-induced autophagy through inhibiting PI3K-Akt-mTOR and activating MAPK/ERK pathways, thereby reducing cisplatin chemosensitivity in cervical cancer cells.\",\n      \"method\": \"ChIP, promoter binding assays, siRNA/overexpression, autophagy assays, PI3K-Akt-mTOR/MAPK signaling analysis, cisplatin sensitivity assays in vitro and in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct promoter binding, multiple signaling pathway assays; single lab\",\n      \"pmids\": [\"34930918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Sirt6 deacetylase downregulates Sox6 by increasing CREB transcription; Sirt6 muscle-specific knockout reduces while transgenic overexpression increases mitochondrial oxidative capacity; Sox6 acts downstream of Sirt6-CREB as the key repressor of slow-fiber genes whose suppression shifts muscle toward oxidative fiber type.\",\n      \"method\": \"Muscle-specific Sirt6 knockout and transgenic mice, gene expression analysis, CREB ChIP/reporter assays, exercise performance assays, Sirt6 activator treatment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in multiple mouse models (KO and transgenic), ChIP/reporter for CREB→Sox6 axis, pharmacological validation; multiple orthogonal approaches\",\n      \"pmids\": [\"35379817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Sox6 binds to the leucine zipper region of Solt (a novel testis-specific protein) via Sox6's leucine zipper; co-expression of Solt with Sox6 (fused to VP16 transactivation domain) enhances reporter gene expression driven by Sox binding sites in a Ca2+/calmodulin-dependent protein kinase IV-dependent manner.\",\n      \"method\": \"Far-Western blot, yeast two-hybrid, in vitro binding assay, transient transfection reporter assay in CHO cells\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid and in vitro binding, reporter assay; functional significance in native context unclear, single lab\",\n      \"pmids\": [\"10996314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In atopic dermatitis, SOX6 (upregulated when miR-335 is lost) recruits SMARCA complex components to epigenetically suppress epidermal differentiation genes; miR-335 directly represses SOX6 and thereby induces keratinocyte differentiation.\",\n      \"method\": \"miRNA target validation (luciferase), ChIP for SMARCA complex, keratinocyte differentiation assays, siRNA knockdown, AD patient skin analysis\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for SMARCA complex recruitment, luciferase validation, functional differentiation assays; single lab\",\n      \"pmids\": [\"32088305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SOX6 induces cellular senescence in cervical cancer via promoting TGFB2 gene expression through MAP4K4-MAPK(JNK/ERK/p38)-ATF2 and WT1-ATF2 pathways, subsequently activating TGFβ2-Smad2/3-p53-p21-Rb signaling; these effects require the HMG domain of SOX6.\",\n      \"method\": \"Overexpression/knockdown, Western blot, co-immunoprecipitation, ChIP, senescence assays, domain mutagenesis (HMG), in vitro and in vivo xenograft\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and Co-IP with domain mutagenesis, multiple pathway readouts; single lab\",\n      \"pmids\": [\"38383842\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SOX6 is an SRY-related HMG-box transcription factor that functions primarily as a transcriptional repressor (and context-dependent activator) by binding pairs of HMG recognition sites, often as a homodimer or L-Sox5 heterodimer via its coiled-coil domain; it recruits co-repressors (CtBP2, HDAC1) to silence targets (Fgf-3, gamma/epsilon-globin, MyHC-beta, cyclin D1, Twist1), cooperates with Sox9 by stabilizing its chromatin occupancy on cartilage super-enhancers (Col2a1, Agc1, miR-140) to drive chondrogenesis, interacts with BCL11A and GATA1 to silence fetal globin in erythropoiesis, promotes erythroid cell survival partly by upregulating Bcl2l1/Bcl-xL and SOCS3, specifies SNc dopamine neuron identity, represses slow-fiber genes in fast-twitch skeletal muscle (regulated in turn by Prdm1/miR-499 and Sirt6-CREB), co-represses PDX1-driven insulin gene expression, is itself negatively autoregulated via a double HMG binding site in its own promoter, and is post-translationally repressed by SUMOylation at two sites that promote its relocalization to PML bodies.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SOX6 is an SRY-related HMG-box transcription factor that orchestrates cell-type specification and differentiation across cartilage, blood, muscle, and the nervous system by binding paired HMG recognition sites, acting predominantly as a transcriptional repressor but also as a context-dependent activator [#0, #20]. Its coiled-coil domain mediates homodimerization and heterodimerization with L-Sox5, which markedly enhances DNA binding to adjacent HMG sites [#0]. In chondrogenesis, SOX6 acts downstream of Sox9 [#2] and, together with L-Sox5, secures and potentiates Sox9 occupancy on cartilage super-enhancers driving Col2a1, aggrecan (Agc1), and miR-140 expression [#11, #23]; genome-wide, SOX6 and SOX9 co-occupy thousands of chondrocyte sites with distinct motif preferences (tandem versus inverted SOX motifs) and are required for super-enhancer target expression [#27]. SOX5/SOX6 are also required cell-autonomously for notochord matrix sheath formation and nucleus pulposus development [#3]. As a repressor, SOX6 recruits co-repressors: CtBP2 via an N-terminal PLNLSS motif to silence Fgf-3 [#1], and HDAC1 to repress Twist1 and reduce promoter histone acetylation [#35]. In erythropoiesis SOX6 silences embryonic/fetal globin genes—directly binding the epsilon-globin promoter [#6] and physically partnering with BCL11A and GATA1 to silence gamma-globin and reorganize the beta-globin locus [#16]—while promoting erythroblast survival and maturation by directly upregulating Bcl2l1/Bcl-xL [#7, #17] and SOCS3 [#19]. In skeletal muscle SOX6 is a direct repressor of slow-fiber sarcomere and developmental genes, its genomic targets being predominantly transcriptionally inactive [#20, #10], a function whose loss in the heart drives pathological fast-twitch gene expression [#26]; SOX6 levels are themselves controlled by upstream Prdm1/miR-499 and Sirt6-CREB circuits [#12, #22, #37]. In the nervous system SOX6 specifies substantia nigra dopamine neuron identity [#24], drives maturation of MGE-derived cortical interneurons downstream of Lhx6 [#13], and segregates pallial from subpallial telencephalic progenitor identity [#14]. SOX6 activity is restrained by negative autoregulation through a double HMG site in its own promoter [#18] and by SUMOylation at two sites that relocalize it to PML bodies [#8]. SOX6 missense-disrupting interactions with SHOX, mutated in Léri-Weill dyschondrosteosis/idiopathic short stature, impair Agc1 enhancer activation, linking the SOX6-SHOX axis to skeletal growth disease [#21].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the biochemical basis of SOX6 function—how it achieves efficient, site-specific DNA binding and cooperates in transcriptional activation.\",\n      \"evidence\": \"Dimerization and EMSA assays plus transgenic enhancer analysis of the Col2a1 chondrocyte element in cell lines and mice\",\n      \"pmids\": [\"9755172\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether dimerization underlies repression as well as activation\", \"Structure of the HMG-DNA complex not determined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined a molecular mechanism for SOX6-mediated repression by identifying a co-repressor recruitment motif.\",\n      \"evidence\": \"Yeast one/two-hybrid, mutagenesis of the PLNLSS motif, and Fgf-3 reporter assays in NIH3T3 cells\",\n      \"pmids\": [\"11504872\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of CtBP2 use across other SOX6 targets not tested\", \"In vivo requirement of the motif not assessed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Placed SOX6 within the chondrogenic transcription factor hierarchy by showing Sox9 acts upstream of its expression.\",\n      \"evidence\": \"Cre/loxP conditional Sox9 knockout with genetic epistasis in mouse\",\n      \"pmids\": [\"12414734\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct regulation of the Sox6 gene by Sox9 not shown\", \"Mechanism of Sox9-dependent induction unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrated essential cell-autonomous SOX5/SOX6 roles in notochord matrix and intervertebral disc development.\",\n      \"evidence\": \"Sox5/Sox6 double-null mouse analysis with marker in situ hybridisation and immunohistochemistry\",\n      \"pmids\": [\"12571105\", \"14530442\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct target genes in notochord not mapped\", \"Cardiomyocyte Prtb interaction (idx 4) of uncertain general significance\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Extended SOX6 to metabolic gene control, showing it co-represses insulin transcription via PDX1.\",\n      \"evidence\": \"Domain-mapped binding, ChIP, histone acetylation and secretion assays in MIN6/INS-1E cells\",\n      \"pmids\": [\"16148004\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance to pancreatic beta-cell function not established\", \"Co-repressor identity at the insulin promoter not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Established SOX6 as a direct globin repressor and survival factor in erythropoiesis, defining dual transcriptional and pro-survival roles.\",\n      \"evidence\": \"EMSA, ChIP, reporter assays and Sox6-deficient and erythroid-specific conditional knockout mice\",\n      \"pmids\": [\"16462943\", \"16627753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-repressor complex at globin promoters not defined in these studies\", \"Mechanism linking SOX6 to F-actin stability unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified SUMOylation as a post-translational switch restraining SOX6 activity and relocalizing it to PML bodies.\",\n      \"evidence\": \"In vitro/in vivo SUMOylation, acceptor-lysine mutagenesis, UBC9 manipulation and immunofluorescence\",\n      \"pmids\": [\"16442531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological signals triggering SOX6 SUMOylation unknown\", \"Functional consequence of PML relocalization on specific targets untested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linked SOX6 to cell-cycle and proliferation control through beta-catenin/HDAC1-dependent cyclin D1 repression, and defined its slow-fiber repressor role in muscle.\",\n      \"evidence\": \"GST pulldown, ChIP, proliferation assays; Sox6 null mice and MyHC-beta promoter analysis\",\n      \"pmids\": [\"17412698\", \"17584907\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cyclin D1 repression operates in vivo not shown\", \"Genome-wide muscle target scope not yet defined at this stage\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved the chondrogenic cooperativity mechanism—L-Sox5/Sox6 enhance Sox9 binding at cartilage enhancers—and identified upstream Prdm1 repression of sox6 in muscle.\",\n      \"evidence\": \"Transgenic enhancer assays, ChIP, EMSA on Agc1/Col2a1; ChIP and ubo mutant epistasis in zebrafish\",\n      \"pmids\": [\"18559420\", \"18535625\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Sox5/6-enhanced Sox9 occupancy unknown\", \"Whether Prdm1 repression of sox6 is conserved in mammals not addressed here\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Established SOX6 as a key regulator of neuronal identity and maturation across interneuron and telencephalic progenitor lineages, and reported an antagonistic splicing-related interaction with DAX-1.\",\n      \"evidence\": \"Sox6 null and conditional knockout mice with electrophysiology and Lhx6 epistasis; yeast two-hybrid and in vitro splicing assays\",\n      \"pmids\": [\"19709629\", \"19657336\", \"19384854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct neuronal target genes of SOX6 not mapped\", \"DAX-1/splicing role (idx 15, Medium) lacks in vivo confirmation\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the SOX6 erythroid regulatory network—BCL11A/GATA1 partnership at the beta-globin locus, direct Bcl2l1 activation, and negative autoregulation—and identified Stat3 as an upstream activator.\",\n      \"evidence\": \"ChIP-chip, 3C, Co-IP, conditional KO, EMSA, autoregulatory site analysis; Stat3 ChIP/reporter in P19 cells\",\n      \"pmids\": [\"20395365\", \"20711497\", \"20852263\", \"21094641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Bcl2l1 regulation (idx 17, Medium) lacks direct ChIP in that study\", \"Stat3-Sox6 link (idx 31, Medium) shown in single cell model\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided genome-wide proof that SOX6 acts as a direct transcriptional suppressor in muscle, defined a Prdm1a/miR-499 lineage loop, and linked SHOX disease mutations to the SOX6 chondrogenic complex.\",\n      \"evidence\": \"Sox6/Pol II ChIP-seq with muscle-specific KO; zebrafish cis-regulatory and miR-499 analysis; SHOX Co-IP, domain mapping and patient mutation reporter assays\",\n      \"pmids\": [\"21985497\", \"21880783\", \"21262861\", \"21263153\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-repressor machinery driving genome-wide muscle suppression not resolved\", \"SOCS3 activation (idx 19) tested mainly in overexpression contexts\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended chondrogenic cooperativity to a microRNA target, showing L-Sox5/Sox6 potentiate Sox9 activation of miR-140.\",\n      \"evidence\": \"Transgenic reporter, ChIP and binding-site mutagenesis of the pri-miR-140 promoter\",\n      \"pmids\": [\"22547066\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether miR-140 mediates downstream SOX6 chondrogenic effects not addressed\", \"Quantitative contribution of SOX6 versus SOX9 not separated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established SOX6 as a specifier of substantia nigra dopamine neuron identity and revealed a Sox2-Sox6 feedback loop controlling neural progenitor differentiation timing.\",\n      \"evidence\": \"Conditional KO with Otx2 epistasis and dopamine measurement; Sox2 ChIP-on-chip with gain/loss-of-function\",\n      \"pmids\": [\"25127144\", \"24501124\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct SOX6 targets defining SNc identity not identified\", \"Sox2-Sox6 loop (idx 25, Medium) characterized in one system\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Broadened SOX6's regulatory logic—stage-dependent and partner-dependent (Nfix) muscle control, oligodendrocyte migration via Pdgfra, a cardiac Trbp/miR-208a→Sox6 disease axis, genome-wide chondrocyte super-enhancer co-occupancy with SOX9, and a tumor-suppressive p14ARF-p53 mechanism.\",\n      \"evidence\": \"ChIP/reporter with Nfix; double conditional KO; Trbp KO with Sox6 rescue/phenocopy mice; SOX6/SOX9 ChIP-seq and super-enhancer analysis; Co-IP, ChIP and xenografts\",\n      \"pmids\": [\"27880909\", \"26345464\", \"26029872\", \"26150426\", \"26119940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism switching SOX6 between activator and repressor states incompletely defined\", \"p14ARF-p53 tumor mechanism (idx 30, Medium) from single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Integrated SOX6 into broader physiological and disease circuits—adipogenesis, juxtaglomerular renin cell differentiation, atopic dermatitis epidermal control, cancer senescence/autophagy, and the Sirt6-CREB-Sox6 oxidative muscle axis.\",\n      \"evidence\": \"Differentiation assays, conditional KO, ChIP for SMARCA/CREB, signaling and senescence assays, multiple mouse models\",\n      \"pmids\": [\"26893351\", \"31760770\", \"32088305\", \"34930918\", \"38383842\", \"35379817\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Several disease mechanisms (adipogenesis, AD, cancer pathways) rest on single-lab studies\", \"Direct chromatin targets in non-canonical tissues not comprehensively mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SOX6 is switched between transcriptional repressor and activator states, and what co-factor and chromatin context determines target selectivity genome-wide, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural or biochemical model for activator-versus-repressor switching\", \"Full co-repressor/co-activator complex composition at most targets undefined\", \"Role of SUMOylation and PML relocalization in target-specific regulation in vivo untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 6, 10, 20, 27]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 6, 18, 20, 27]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [11, 23, 5, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 20, 27]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [8, 30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 6, 20, 27]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 3, 13, 14, 24, 28]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [5, 9, 16, 35, 39]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SOX5\", \"SOX9\", \"CTBP2\", \"HDAC1\", \"BCL11A\", \"GATA1\", \"CTNNB1\", \"PDX1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":10,"faith_total":10,"faith_pct":100.0}}