Affinage

SOX6

Transcription factor SOX-6 · UniProt P35712

Length
828 aa
Mass
91.9 kDa
Annotated
2026-06-10
100 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 10/10 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1998 High

    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

    PMID:9755172

    Open questions at the time
    • Did not resolve whether dimerization underlies repression as well as activation
    • Structure of the HMG-DNA complex not determined
  2. 2001 High

    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

    PMID:11504872

    Open questions at the time
    • Generality of CtBP2 use across other SOX6 targets not tested
    • In vivo requirement of the motif not assessed
  3. 2002 High

    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

    PMID:12414734

    Open questions at the time
    • Direct regulation of the Sox6 gene by Sox9 not shown
    • Mechanism of Sox9-dependent induction unresolved
  4. 2003 High

    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

    PMID:12571105 PMID:14530442

    Open questions at the time
    • Direct target genes in notochord not mapped
    • Cardiomyocyte Prtb interaction (idx 4) of uncertain general significance
  5. 2005 High

    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

    PMID:16148004

    Open questions at the time
    • In vivo relevance to pancreatic beta-cell function not established
    • Co-repressor identity at the insulin promoter not defined
  6. 2006 High

    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

    PMID:16462943 PMID:16627753

    Open questions at the time
    • Co-repressor complex at globin promoters not defined in these studies
    • Mechanism linking SOX6 to F-actin stability unresolved
  7. 2006 High

    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

    PMID:16442531

    Open questions at the time
    • Physiological signals triggering SOX6 SUMOylation unknown
    • Functional consequence of PML relocalization on specific targets untested
  8. 2007 High

    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

    PMID:17412698 PMID:17584907

    Open questions at the time
    • Whether cyclin D1 repression operates in vivo not shown
    • Genome-wide muscle target scope not yet defined at this stage
  9. 2008 High

    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

    PMID:18535625 PMID:18559420

    Open questions at the time
    • Structural basis of Sox5/6-enhanced Sox9 occupancy unknown
    • Whether Prdm1 repression of sox6 is conserved in mammals not addressed here
  10. 2009 High

    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

    PMID:19384854 PMID:19657336 PMID:19709629

    Open questions at the time
    • Direct neuronal target genes of SOX6 not mapped
    • DAX-1/splicing role (idx 15, Medium) lacks in vivo confirmation
  11. 2010 High

    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

    PMID:20395365 PMID:20711497 PMID:20852263 PMID:21094641

    Open questions at the time
    • Bcl2l1 regulation (idx 17, Medium) lacks direct ChIP in that study
    • Stat3-Sox6 link (idx 31, Medium) shown in single cell model
  12. 2011 High

    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

    PMID:21262861 PMID:21263153 PMID:21880783 PMID:21985497

    Open questions at the time
    • Co-repressor machinery driving genome-wide muscle suppression not resolved
    • SOCS3 activation (idx 19) tested mainly in overexpression contexts
  13. 2012 High

    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

    PMID:22547066

    Open questions at the time
    • Whether miR-140 mediates downstream SOX6 chondrogenic effects not addressed
    • Quantitative contribution of SOX6 versus SOX9 not separated
  14. 2014 High

    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

    PMID:24501124 PMID:25127144

    Open questions at the time
    • Direct SOX6 targets defining SNc identity not identified
    • Sox2-Sox6 loop (idx 25, Medium) characterized in one system
  15. 2015 High

    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

    PMID:26029872 PMID:26119940 PMID:26150426 PMID:26345464 PMID:27880909

    Open questions at the time
    • Mechanism switching SOX6 between activator and repressor states incompletely defined
    • p14ARF-p53 tumor mechanism (idx 30, Medium) from single lab
  16. 2022 Medium

    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

    PMID:26893351 PMID:31760770 PMID:32088305 PMID:34930918 PMID:35379817 PMID:38383842

    Open questions at the time
    • Several disease mechanisms (adipogenesis, AD, cancer pathways) rest on single-lab studies
    • Direct chromatin targets in non-canonical tissues not comprehensively mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SOX6 is switched between transcriptional repressor and activator states, and what co-factor and chromatin context determines target selectivity genome-wide, remains unresolved.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 5 GO:0098772 molecular function regulator activity 4
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 2
Pathway
R-HSA-1266738 Developmental Biology 6 R-HSA-4839726 Chromatin organization 5 R-HSA-74160 Gene expression (Transcription) 5
Partners
BCL11ACTBP2CTNNB1GATA1HDAC1PDX1SOX5SOX9

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 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. Protein dimerization assays, DNA binding/EMSA, reporter gene (luciferase) assays in 10T1/2 and MC615 cells, transgenic mouse enhancer analysis The EMBO journal High 9755172
2001 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. Yeast one-hybrid screen, yeast two-hybrid screen, reporter gene assays in NIH3T3 cells, site-directed mutagenesis, co-expression studies, in situ hybridisation Nucleic acids research High 11504872
2002 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. Cre/loxP conditional knockout mice, in situ hybridisation, immunohistochemistry, genetic epistasis Genes & development High 12414734
2003 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. Sox5/Sox6 double-null mouse genetic analysis, in situ hybridisation, immunohistochemistry, gene expression analysis Development (Cambridge, England) High 12571105
2003 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. Yeast two-hybrid, co-immunoprecipitation, P19CL6 cardiomyocyte differentiation model, noggin-expressing stable cells, in vivo comparison of WT vs p100H mutant mice Nucleic acids research Medium 14530442
2005 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. 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 The Journal of biological chemistry High 16148004
2006 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. EMSA, ChIP, transfection reporter assays in GM979 cells, Sox6-deficient mouse analysis PLoS genetics High 16462943
2006 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. 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 Blood High 16627753
2006 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. In vitro and in vivo SUMOylation assays, site-directed mutagenesis of SUMO acceptor lysines, reporter gene assays, siRNA, immunofluorescence microscopy FEBS letters High 16442531
2007 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. siRNA, retroviral overexpression, luciferase reporter assay, in vitro binding (GST pulldown), ChIP, HDAC inhibitor, co-immunoprecipitation The Journal of biological chemistry High 17412698
2007 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. Sox6 null mouse phenotype analysis, siRNA knockdown in myotubes, MyHC-beta promoter analysis, reporter assays Developmental dynamics High 17584907
2008 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. Transgenic mouse enhancer assays, ChIP, EMSA, reporter gene assays, site-directed mutagenesis of cis-elements Molecular and cellular biology High 18559420
2008 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. ChIP in zebrafish embryos, ubo mutant analysis, gene expression assays, epistasis EMBO reports High 18535625
2009 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. Sox6 null mouse analysis, electrophysiology, genetic epistasis with Lhx6 null, immunostaining, position analysis Neuron High 19709629
2009 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. Sox6 conditional knockout mice, immunohistochemistry, in situ hybridisation, gene expression profiling Nature neuroscience High 19657336
2009 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. Yeast two-hybrid, biochemical co-precipitation, in vivo and in vitro splicing assays Developmental dynamics Medium 19384854
2010 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. ChIP-chip, chromosome conformation capture (3C), co-immunoprecipitation, siRNA knockdown in adult erythroid progenitors Genes & development High 20395365
2010 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. Conditional Sox6 knockout (Sox6fl/flCaggCreER and Sox6fl/flErGFPCre), tamoxifen induction, gene expression profiling, in vitro erythroblast assays PloS one Medium 20711497
2010 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. Bioinformatic genome-wide search, EMSA, ChIP, luciferase reporter assays in K562 and primary erythroblasts, chromatin accessibility (PstI restriction), lentiviral transduction Nucleic acids research High 20852263
2011 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. Lentiviral overexpression in K562 and primary human erythroid cultures, EMSA, ChIP, reporter assays, SOCS3 rescue experiment Blood High 21263153
2011 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. ChIP-seq (Sox6 and RNA Pol II), muscle-specific Sox6 knockout mice, gene expression profiling BMC developmental biology High 21985497
2011 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. Yeast two-hybrid, co-immunoprecipitation in human cells, immunohistochemistry on human fetal growth plate, domain mutagenesis, luciferase reporter assays Human molecular genetics High 21262861
2011 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. Cis-regulatory reporter transgenics, morpholino knockdown, miR-499 analysis, Prdm1a-dependent expression assays in zebrafish Development (Cambridge, England) High 21880783
2012 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. Transgenic mouse reporter assays, ChIP, reporter gene assays in chondrocyte cell lines, binding site mutagenesis The Journal of biological chemistry High 22547066
2014 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. Sox6 conditional knockout, immunohistochemistry, in situ hybridisation, dopamine level measurement, axonal tracing Cell reports High 25127144
2014 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. ChIP-on-chip for Sox2, gain- and loss-of-function in neural progenitor cells, in vivo expression analysis in ventricular zone Proceedings of the National Academy of Sciences of the United States of America Medium 24501124
2015 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. Cardiac-specific Trbp conditional KO, Sox6 knockdown rescue, Sox6 transgenic overexpression, miR-208a transgenic rescue, gene expression profiling, cardiac function measurement Nature genetics High 26029872
2015 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. Genome-wide ChIP-seq for SOX6 and SOX9 in RCS cells, motif analysis, super-enhancer analysis, in vivo expression validation Nucleic acids research High 26150426
2015 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. CNS-specific Sox5/Sox6 double conditional knockout mice, gene expression analysis, Pdgf responsiveness assays, immunostaining Glia High 26345464
2015 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. ChIP, reporter gene assays, Sox6/Nfix co-expression, gain/loss-of-function in myoblasts, zebrafish nfixa/sox6 conservation analysis Cell reports High 27880909
2015 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. Co-immunoprecipitation, immunocytofluorescence, ChIP-PCR, Western blot, cell proliferation assays in vitro and in vivo xenograft Oncogene Medium 26119940
2010 Stat3 directly binds the Sox6 promoter in response to ligand stimulation and is required for Sox6 expression during neuronal differentiation of P19 cells. ChIP, reporter gene assay, RNAi knockdown, P19 neuronal differentiation model FEBS letters Medium 21094641
2013 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. ChIP, retroviral overexpression, siRNA knockdown, neurosphere assays, immunofluorescence, Western blot PloS one Medium 24066135
2016 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. Adipocyte differentiation from MSCs (umbilical cord), gene expression analysis, co-immunoprecipitation (SOX6-β-catenin), CpG methylation analysis, SOX6 binding assays Development (Cambridge, England) Medium 26893351
2019 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. Conditional Sox6 knockout in Ren1d+ cells, in vitro differentiation assays, in vivo dietary manipulation (low-Na/furosemide), renin immunostaining, gene expression American journal of physiology. Renal physiology Medium 31760770
2018 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. ChIP, quantitative ChIP, luciferase reporter assay, co-immunoprecipitation, cell invasion/migration assays, in vivo xenograft, HDAC1 interaction Journal of cellular and molecular medicine Medium 29369542
2021 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. ChIP, promoter binding assays, siRNA/overexpression, autophagy assays, PI3K-Akt-mTOR/MAPK signaling analysis, cisplatin sensitivity assays in vitro and in vivo xenograft Cell death & disease Medium 34930918
2022 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. Muscle-specific Sirt6 knockout and transgenic mice, gene expression analysis, CREB ChIP/reporter assays, exercise performance assays, Sirt6 activator treatment Nature communications High 35379817
2000 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. Far-Western blot, yeast two-hybrid, in vitro binding assay, transient transfection reporter assay in CHO cells FEBS letters Low 10996314
2020 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. miRNA target validation (luciferase), ChIP for SMARCA complex, keratinocyte differentiation assays, siRNA knockdown, AD patient skin analysis The Journal of allergy and clinical immunology Medium 32088305
2024 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. Overexpression/knockdown, Western blot, co-immunoprecipitation, ChIP, senescence assays, domain mutagenesis (HMG), in vitro and in vivo xenograft Molecular oncology Medium 38383842

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes & development 1412 12414734
1998 A new long form of Sox5 (L-Sox5), Sox6 and Sox9 are coexpressed in chondrogenesis and cooperatively activate the type II collagen gene. The EMBO journal 662 9755172
2010 Transcriptional silencing of {gamma}-globin by BCL11A involves long-range interactions and cooperation with SOX6. Genes & development 309 20395365
2001 L-Sox5, Sox6 and Sox9 control essential steps of the chondrocyte differentiation pathway. Osteoarthritis and cartilage 296 11680692
2004 The combination of SOX5, SOX6, and SOX9 (the SOX trio) provides signals sufficient for induction of permanent cartilage. Arthritis and rheumatism 279 15529345
2008 L-Sox5 and Sox6 drive expression of the aggrecan gene in cartilage by securing binding of Sox9 to a far-upstream enhancer. Molecular and cellular biology 247 18559420
2015 The transcription factors SOX9 and SOX5/SOX6 cooperate genome-wide through super-enhancers to drive chondrogenesis. Nucleic acids research 226 26150426
2009 The cell-intrinsic requirement of Sox6 for cortical interneuron development. Neuron 175 19709629
2009 SOX6 controls dorsal progenitor identity and interneuron diversity during neocortical development. Nature neuroscience 164 19657336
2003 Sox5 and Sox6 are required for notochord extracellular matrix sheath formation, notochord cell survival and development of the nucleus pulposus of intervertebral discs. Development (Cambridge, England) 137 12571105
2009 The SoxD transcription factors--Sox5, Sox6, and Sox13--are key cell fate modulators. The international journal of biochemistry & cell biology 135 19647094
1995 The Sry-related HMG box-containing gene Sox6 is expressed in the adult testis and developing nervous system of the mouse. Nucleic acids research 132 7567444
2014 Sox6 and Otx2 control the specification of substantia nigra and ventral tegmental area dopamine neurons. Cell reports 124 25127144
2007 SOX6 suppresses cyclin D1 promoter activity by interacting with beta-catenin and histone deacetylase 1, and its down-regulation induces pancreatic beta-cell proliferation. The Journal of biological chemistry 124 17412698
2007 Sox6 is required for normal fiber type differentiation of fetal skeletal muscle in mice. Developmental dynamics : an official publication of the American Association of Anatomists 121 17584907
2008 Prdm1- and Sox6-mediated transcriptional repression specifies muscle fibre type in the zebrafish embryo. EMBO reports 106 18535625
2006 Sox6 directly silences epsilon globin expression in definitive erythropoiesis. PLoS genetics 101 16462943
2013 MiR-499 regulates cell proliferation and apoptosis during late-stage cardiac differentiation via Sox6 and cyclin D1. PloS one 91 24040263
2014 Mir-208 promotes cell proliferation by repressing SOX6 expression in human esophageal squamous cell carcinoma. Journal of translational medicine 79 25023649
2010 Characterization of tumor-suppressive function of SOX6 in human esophageal squamous cell carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 74 21084391
2006 Sox6 cell-autonomously stimulates erythroid cell survival, proliferation, and terminal maturation and is thereby an important enhancer of definitive erythropoiesis during mouse development. Blood 73 16627753
2000 Sox6 is a candidate gene for p100H myopathy, heart block, and sudden neonatal death. Proceedings of the National Academy of Sciences of the United States of America 73 10760285
2012 L-Sox5 and Sox6 proteins enhance chondrogenic miR-140 microRNA expression by strengthening dimeric Sox9 activity. The Journal of biological chemistry 70 22547066
2011 Sox6, jack of all trades: a versatile regulatory protein in vertebrate development. Developmental dynamics : an official publication of the American Association of Anatomists 70 21495113
2005 SOX6 attenuates glucose-stimulated insulin secretion by repressing PDX1 transcriptional activity and is down-regulated in hyperinsulinemic obese mice. The Journal of biological chemistry 70 16148004
2016 SOX6 and PDCD4 enhance cardiomyocyte apoptosis through LPS-induced miR-499 inhibition. Apoptosis : an international journal on programmed cell death 68 26659076
2021 Sox6 expression distinguishes dorsally and ventrally biased dopamine neurons in the substantia nigra with distinctive properties and embryonic origins. Cell reports 66 34758317
2019 miRNA‑342 suppresses renal interstitial fibrosis in diabetic nephropathy by targeting SOX6. International journal of molecular medicine 66 31746345
2001 Accelerated up-regulation of L-Sox5, Sox6, and Sox9 by BMP-2 gene transfer during murine fracture healing. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 65 11585348
2001 SOX6 binds CtBP2 to repress transcription from the Fgf-3 promoter. Nucleic acids research 64 11504872
2011 Sox6 enhances erythroid differentiation in human erythroid progenitors. Blood 60 21263153
2015 Trbp regulates heart function through microRNA-mediated Sox6 repression. Nature genetics 58 26029872
2021 MAP4K4 mediates the SOX6-induced autophagy and reduces the chemosensitivity of cervical cancer. Cell death & disease 57 34930918
2010 Synovial joint morphogenesis requires the chondrogenic action of Sox5 and Sox6 in growth plate and articular cartilage. Developmental biology 57 20206616
2015 Transcription factors Sox5 and Sox6 exert direct and indirect influences on oligodendroglial migration in spinal cord and forebrain. Glia 55 26345464
2003 Sox6 regulation of cardiac myocyte development. Nucleic acids research 55 14530442
2020 microRNA-499a promotes the progression and chemoresistance of cervical cancer cells by targeting SOX6. Apoptosis : an international journal on programmed cell death 54 31938895
2011 Prdm1a and miR-499 act sequentially to restrict Sox6 activity to the fast-twitch muscle lineage in the zebrafish embryo. Development (Cambridge, England) 54 21880783
2004 Identification of a human glioma antigen, SOX6, recognized by patients' sera. Oncogene 54 14691456
2019 MicroRNA-223 is essential for maintaining functional β-cell mass during diabetes through inhibiting both FOXO1 and SOX6 pathways. The Journal of biological chemistry 51 31118273
2015 Role of p14ARF-HDM2-p53 axis in SOX6-mediated tumor suppression. Oncogene 51 26119940
2007 Transcriptional activation of cartilage oligomeric matrix protein by Sox9, Sox5, and Sox6 transcription factors and CBP/p300 coactivators. Frontiers in bioscience : a journal and virtual library 51 17485346
2015 MicroRNA-766 targeting regulation of SOX6 expression promoted cell proliferation of human colorectal cancer. OncoTargets and therapy 50 26543373
2020 Circ_WBSCR17 aggravates inflammatory responses and fibrosis by targeting miR-185-5p/SOX6 regulatory axis in high glucose-induced human kidney tubular cells. Life sciences 49 32798559
2011 Genome-wide mapping of Sox6 binding sites in skeletal muscle reveals both direct and indirect regulation of muscle terminal differentiation by Sox6. BMC developmental biology 49 21985497
2020 Belinostat resolves skin barrier defects in atopic dermatitis by targeting the dysregulated miR-335:SOX6 axis. The Journal of allergy and clinical immunology 48 32088305
2022 Sirt6 reprograms myofibers to oxidative type through CREB-dependent Sox6 suppression. Nature communications 46 35379817
2019 MiR-499 inhibited hypoxia/reoxygenation induced cardiomyocytes injury by targeting SOX6. Biotechnology letters 46 31076992
2011 SHOX interacts with the chondrogenic transcription factors SOX5 and SOX6 to activate the aggrecan enhancer. Human molecular genetics 46 21262861
2016 The transcription factor SOX6 contributes to the developmental origins of obesity by promoting adipogenesis. Development (Cambridge, England) 45 26893351
2020 Activation of the SOX-5, SOX-6, and SOX-9 Trio of Transcription Factors Using a Gene-Activated Scaffold Stimulates Mesenchymal Stromal Cell Chondrogenesis and Inhibits Endochondral Ossification. Advanced healthcare materials 42 32329217
2018 miR-671 promotes prostate cancer cell proliferation by targeting tumor suppressor SOX6. European journal of pharmacology 40 29355560
2015 The role of Sox6 in zebrafish muscle fiber type specification. Skeletal muscle 39 25671076
2019 LncRNA Riken-201 and Riken-203 modulates neural development by regulating the Sox6 through sequestering miRNAs. Cell proliferation 38 30667104
2015 MicroRNA-499 expression distinctively correlates to target genes sox6 and rod1 profiles to resolve the skeletal muscle phenotype in Nile tilapia. PloS one 38 25793727
2014 Positive feedback loop between Sox2 and Sox6 inhibits neuronal differentiation in the developing central nervous system. Proceedings of the National Academy of Sciences of the United States of America 38 24501124
2001 Cloning, characterization and chromosome mapping of the human SOX6 gene. Gene 38 11255018
2019 MicroRNA-129-5p alleviates nerve injury and inflammatory response of Alzheimer's disease via downregulating SOX6. Cell cycle (Georgetown, Tex.) 37 31564203
2011 Genetic variants in the SOX6 gene are associated with bone mineral density in both Caucasian and Chinese populations. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 36 21625884
2019 UBE2S mediates tumor progression via SOX6/β-Catenin signaling in endometrial cancer. The international journal of biochemistry & cell biology 35 30690078
2018 Identification of Sox6 as a regulator of pancreatic cancer development. Journal of cellular and molecular medicine 35 29369542
2010 Identification of HLA-A2- and A24-restricted T-cell epitopes derived from SOX6 expressed in glioma stem cells for immunotherapy. International journal of cancer 33 19728337
2019 Long non-coding RNA CHRF modulates the progression of cerebral ischemia/reperfusion injury via miR-126/SOX6 signaling pathway. Biochemical and biophysical research communications 32 31060778
2016 Nfix Induces a Switch in Sox6 Transcriptional Activity to Regulate MyHC-I Expression in Fetal Muscle. Cell reports 32 27880909
2016 Downregulation of long non-coding RNA H19 promotes P19CL6 cells proliferation and inhibits apoptosis during late-stage cardiac differentiation via miR-19b-modulated Sox6. Cell & bioscience 32 27895893
2018 Disruption of SOX6 gene using CRISPR/Cas9 technology for gamma-globin reactivation: An approach towards gene therapy of β-thalassemia. Journal of cellular biochemistry 31 30010219
2006 Generation of mice harboring a Sox6 conditional null allele. Genesis (New York, N.Y. : 2000) 31 16652367
2018 Copy Number Variation in SOX6 Contributes to Chicken Muscle Development. Genes 30 29342086
2017 MicroRNA-499-5p regulates porcine myofiber specification by controlling Sox6 expression. Animal : an international journal of animal bioscience 30 28490391
2010 Sox6 is necessary for efficient erythropoiesis in adult mice under physiological and anemia-induced stress conditions. PloS one 30 20711497
2004 Sox6 overexpression causes cellular aggregation and the neuronal differentiation of P19 embryonic carcinoma cells in the absence of retinoic acid. FEBS letters 30 14988021
2004 Expression of a transcriptional factor, SOX6, in human gliomas. Brain tumor pathology 30 15696967
2021 Knockdown of lncRNA XIST inhibited apoptosis and inflammation in renal fibrosis via microRNA-19b-mediated downregulation of SOX6. Molecular immunology 29 34461493
2017 The role of Sox6 and Netrin-1 in ovarian cancer cell growth, invasiveness, and angiogenesis. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 29 28475012
2021 Circular RNA circ_0000712 regulates high glucose-induced apoptosis, inflammation, oxidative stress, and fibrosis in (DN) by targeting the miR-879-5p/SOX6 axis. Endocrine journal 27 33980772
2017 miR-96 targets SOX6 and promotes proliferation, migration, and invasion of hepatocellular carcinoma. Biochemistry and cell biology = Biochimie et biologie cellulaire 27 28892647
2013 Sox6 up-regulation by macrophage migration inhibitory factor promotes survival and maintenance of mouse neural stem/progenitor cells. PloS one 26 24066135
2026 Curcumin Suppresses Cell Proliferation, Migration, and Invasion Through Modulating miR-21-5p/SOX6 Axis in Hepatocellular Carcinoma. Cancer biotherapy & radiopharmaceuticals 25 32757994
2010 Stat3 is essential for neuronal differentiation through direct transcriptional regulation of the Sox6 gene. FEBS letters 24 21094641
2006 Repression of SOX6 transcriptional activity by SUMO modification. FEBS letters 24 16442531
2020 De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas. American journal of human genetics 23 32442410
2019 MicroRNA-103 contributes to osteoarthritis development by targeting Sox6. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 23 31302420
2024 MAP4K4 and WT1 mediate SOX6-induced cellular senescence by synergistically activating the ATF2-TGFβ2-Smad2/3 signaling pathway in cervical cancer. Molecular oncology 21 38383842
2019 Gastric cancer proliferation and invasion is reduced by macrocalyxin C via activation of the miR-212-3p/Sox6 Pathway. Cellular signalling 21 31726103
2019 SOX6 suppresses the development of lung adenocarcinoma by regulating expression of p53, p21CIPI , cyclin D1 and β-catenin. FEBS open bio 21 31729835
2017 PDK2 promotes chondrogenic differentiation of mesenchymal stem cells by upregulation of Sox6 and activation of JNK/MAPK/ERK pathway. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 21 28225870
2005 Balanced translocation in a patient with craniosynostosis disrupts the SOX6 gene and an evolutionarily conserved non-transcribed region. Journal of medical genetics 21 16258006
2021 Stanniocalcin-2 promotes cell EMT and glycolysis via activating ITGB2/FAK/SOX6 signaling pathway in nasopharyngeal carcinoma. Cell biology and toxicology 20 33797657
2020 Emerging roles of Sox6 in the renal and cardiovascular system. Physiological reports 20 33230925
2015 MiR-202 promotes endometriosis by regulating SOX6 expression. International journal of clinical and experimental medicine 20 26770366
2010 A highly conserved SOX6 double binding site mediates SOX6 gene downregulation in erythroid cells. Nucleic acids research 20 20852263
2009 DAX-1 and SOX6 molecular interplay results in an antagonistic effect in pre-mRNA splicing. Developmental dynamics : an official publication of the American Association of Anatomists 20 19384854
2000 Characterization of Solt, a novel SoxLZ/Sox6 binding protein expressed in adult mouse testis. FEBS letters 20 10996314
2022 Sox6 Differentially Regulates Inherited Myogenic Abilities and Muscle Fiber Types of Satellite Cells Derived from Fast- and Slow-Type Muscles. International journal of molecular sciences 19 36232654
2019 Sox6 as a new modulator of renin expression in the kidney. American journal of physiology. Renal physiology 19 31760770
2019 miR-380-3p regulates melanogenesis by targeting SOX6 in melanocytes from alpacas (Vicugna pacos). BMC genomics 19 31823726
2018 SOX6 is downregulated in osteosarcoma and suppresses the migration, invasion and epithelial-mesenchymal transition via TWIST1 regulation. Molecular medicine reports 19 29512775
2017 Inducing indel mutation in the SOX6 gene by zinc finger nuclease for gamma reactivation: An approach towards gene therapy of beta thalassemia. Journal of cellular biochemistry 19 28941328
2014 Functional analyses reveal the essential role of SOX6 and RUNX2 in the communication of chondrocyte and osteoblast. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 19 25212673
2022 Transcriptome sequencing analysis of the role of miR-499-5p and SOX6 in chicken skeletal myofiber specification. Frontiers in genetics 18 36186474

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