Affinage

SOX2

Transcription factor SOX-2 · UniProt P48431

Length
317 aa
Mass
34.3 kDa
Annotated
2026-04-28
100 papers in source corpus 36 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SOX2 is a pioneer transcription factor that opens chromatin, cooperates with context-dependent partners to regulate gene expression, and is tightly controlled by post-translational modifications governing its stability and nuclear localization. Structurally, its HMG domain binds nucleosomal DNA at superhelical location 2, distorting it to detach terminal DNA from the histone octamer and displacing the H4 N-terminal tail, thereby mechanistically explaining chromatin opening; acute SOX2 depletion causes rapid loss of thousands of accessible chromatin sites, demonstrating that this pioneer activity is continuously required (PMID:32350470, PMID:37691488). SOX2 partners with OCT4 in pluripotent cells, p63 in squamous cell carcinomas, and PAX6 in lens/neural development to co-occupy and activate distinct enhancer repertoires, and its intrinsically disordered C-terminal region undergoes DNA/nucleosome-induced conformational rearrangements that expose activation domains critical for transcription (PMID:32327602, PMID:24590290, PMID:17140559, PMID:38365983). SOX2 protein levels are governed by competing ubiquitin ligases (CUL4A–COP1, WWP2, UBE2S) and deubiquitinases (OTUD7B, USP9x, TRIM26), and by phosphorylation via CDK1, CDK2, and AKT that controls nuclear import and transcriptional competence (PMID:30405104, PMID:34732716, PMID:26292759, PMID:26139602, PMID:30297536).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2006 High

    Establishing that SOX2 functions cooperatively with POU-domain partners on specific enhancers resolved how SOX2 achieves target selectivity — SOX2 forms a complex with Oct-1 to cooperatively bind and transactivate the Pax6 lens ectoderm enhancer, and separately acts upstream of Notch signaling in neural progenitors.

    Evidence Cooperative DNA binding/transactivation assays and transgenic mouse enhancer analysis (lens); overexpression/dominant-negative HMG constructs in neural progenitors (Notch)

    PMID:16631155 PMID:17140559

    Open questions at the time
    • Whether SOX2–Oct-1 complex uses the same interface as SOX2–OCT4 was not determined
    • Direct binding of SOX2 to Notch pathway gene promoters was not shown
  2. 2007 Medium

    Demonstrating cooperative SOX2–PAX6 binding on a minimal enhancer element established that SOX2 uses distinct partner-dependent DNA recognition modes at different regulatory elements.

    Evidence Enhancer deletion/mutagenesis and transactivation assays on the Sox2 N-3 enhancer

    PMID:17825048

    Open questions at the time
    • Structural basis of SOX2–PAX6 cooperativity was not resolved
    • In vivo validation of the N-3 minimal element was not performed
  3. 2012 Medium

    Showing that SUMOylation of SOX2 by PIAS3 impairs the SOX2–OCT4 interaction and suppresses Nanog expression revealed that post-translational modifications can modulate the core pluripotency transcription factor complex.

    Evidence Co-IP and Nanog luciferase reporter with SUMO pathway manipulation in ES cells

    PMID:22745796

    Open questions at the time
    • The specific SUMOylation site(s) on SOX2 were not mapped
    • In vivo developmental consequence of SOX2 SUMOylation was not tested
  4. 2014 High

    Identifying p63 as the preferred SOX2 partner in squamous cell carcinomas (replacing OCT4) demonstrated that SOX2 rewires its cistrome in a cell-type-dependent manner to drive oncogenic programs including ETV4 activation.

    Evidence ChIP-seq co-occupancy mapping, co-IP, and siRNA knockdown across multiple SCC lines

    PMID:24590290

    Open questions at the time
    • Structural basis of the SOX2–p63 interaction was not resolved
    • Whether SOX2–p63 cooperation requires pioneer-factor chromatin opening was not tested
  5. 2014 Medium

    Showing that SOX2 directly binds and represses Lef-1 transcription established SOX2 as a transcriptional repressor at specific loci, not exclusively an activator, and linked it to Wnt pathway antagonism in airway epithelium.

    Evidence ChIP, DNA-binding assay, transcriptional reporter, and conditional Sox2 deletion in primary airway epithelium

    PMID:24487391

    Open questions at the time
    • Co-repressor complexes recruited by SOX2 at repressed loci were not identified
    • Genome-wide scope of SOX2-mediated repression was not assessed
  6. 2015 High

    A burst of studies on SOX2 post-translational regulation revealed that CDK2 phosphorylates SOX2 at S39/S253 to promote reprogramming, UBE2S marks SOX2 with K11-linked polyubiquitin at K123 for proteasomal degradation, AKT controls SOX2 nuclear import and stability, and SOX2 represses Hippo pathway genes Nf2/WWC1 to activate YAP in cancer stem cells — collectively establishing that SOX2 protein dosage is actively and dynamically tuned.

    Evidence In vitro kinase assays with site-directed mutagenesis (CDK2); ubiquitination assay with K123 mutagenesis and linkage-type identification (UBE2S); co-IP with subcellular fractionation and pharmacological rescue (AKT); ChIP plus YAP epistasis in osteosarcoma/GBM (Hippo)

    PMID:25832504 PMID:26139602 PMID:26292759 PMID:26498353

    Open questions at the time
    • Cross-talk between phosphorylation and ubiquitination was not examined
    • Identity of the E3 ligase working with UBE2S was not established
    • Whether AKT directly phosphorylates SOX2 or acts indirectly was not resolved
  7. 2017 Medium

    RIT1–AKT signaling was shown to phosphorylate SOX2 at T118 to stabilize it and promote hippocampal neurogenesis, while fusion-protein experiments established that SOX2 acts as a transcriptional activator (not repressor) during human fibroblast reprogramming, binding de novo enhancers.

    Evidence RIT1 KO mouse with IGF-1 infusion and phospho-site identification; SOX2-VP16/HP1 fusion reprogramming assays with ChIP-seq

    PMID:28607354 PMID:28813671

    Open questions at the time
    • Whether T118 phosphorylation affects pioneer factor activity on nucleosomes was not tested
    • The relationship between de novo enhancer creation and chromatin opening mechanism was not resolved
  8. 2018 High

    The CUL4A–DET1–COP1 E3 ligase complex and the counteracting deubiquitinase OTUD7B were identified as a balanced ubiquitin–deubiquitin pair controlling SOX2 turnover during neural progenitor differentiation, while CDK1 was shown to phosphorylate SOX2 to promote its nuclear localization and transcriptional activity in cancer.

    Evidence Reciprocal co-IP, in vitro ubiquitylation, COP1/OTUD7B knockdown with NPC differentiation readout; CDK1 kinase-dead mutant plus Sox2 KO rescue in tumor model

    PMID:30297536 PMID:30405104

    Open questions at the time
    • The specific SOX2 lysines targeted by COP1 were not mapped
    • Whether CDK1 and CDK2 phosphorylate the same or different SOX2 residues was not clarified
  9. 2020 High

    Cryo-EM structures of SOX2 (alone and with OCT4) on nucleosomes provided the atomic-level mechanism of pioneer factor activity: SOX2 binds at superhelical location 2, distorts nucleosomal DNA, detaches terminal DNA from the histone octamer, and repositions the H4 tail, while OCT4 uses only one DNA-binding domain and position-dependent distortions differ.

    Evidence Cryo-EM structure determination of SOX2-nucleosome and OCT4-SOX2-nucleosome complexes

    PMID:32327602 PMID:32350470

    Open questions at the time
    • Contribution of the SOX2 disordered domains to nucleosome engagement was not captured in structures
    • How chromatin remodelers collaborate with structural distortion was not addressed
  10. 2020 High

    SOX2 was shown to directly bind RNA through its HMG domain and to interact with RNA helicase DDX5 to inhibit R-loop resolution, revealing a non-transcription-factor function in RNA metabolism and R-loop regulation relevant to reprogramming.

    Evidence In vitro RNA binding assays; UV-crosslinked fRIP-seq in mESCs (RNA binding); co-IP, DRIP-seq, and RNaseH1 epistasis (DDX5/R-loop)

    PMID:32286318 PMID:32704541

    Open questions at the time
    • Functional consequence of SOX2–RNA binding on specific transcripts was not established
    • Whether RNA binding competes with DNA/nucleosome binding in vivo was not determined
  11. 2021 High

    TRIM26 was identified as a non-catalytic stabilizer of SOX2 that competitively blocks the E3 ligase WWP2, and SOX2 was shown to reprogram the esophageal epigenome by co-binding with KLF5 at oncogenes and activating endogenous retroviruses — revealing new layers of SOX2 protein stabilization and cistrome evolution in cancer.

    Evidence Proteomic co-IP/MS, domain mutagenesis, ubiquitination assay in GSCs (TRIM26/WWP2); multi-omic mapping in murine esophageal organoids (cistrome evolution)

    PMID:33972779 PMID:34732716

    Open questions at the time
    • Whether TRIM26-mediated stabilization is regulated by signaling was not addressed
    • How SOX2–KLF5 cooperation is established at the structural level is unknown
  12. 2022 High

    Single-molecule biophysics revealed that SOX2 forms co-condensates with DNA and generates mechanical forces (~7 pN) through its disordered domains, with nucleosomes attenuating this force by sequestering SOX2 — linking phase separation to pioneer factor mechanics.

    Evidence Single-molecule force spectroscopy, FRET, and condensate assays with domain mutants

    PMID:35810158

    Open questions at the time
    • In vivo relevance of condensate-mediated forces to chromatin opening was not demonstrated
    • Whether force generation contributes to nucleosome displacement or is a separate property is unclear
  13. 2023 High

    Acute depletion and in vivo developmental studies established that SOX2 pioneer activity is continuously required to maintain thousands of open chromatin sites, and that SOX2 occupies pre-accessible enhancers in early embryos and dynamically redistributes across pluripotency transitions.

    Evidence Auxin-inducible degron depletion with ATAC-seq in mESCs; CUT&RUN/ChIP-seq across E3.5–E7.5 mouse embryos with genetic loss-of-function

    PMID:37691488 PMID:38096290

    Open questions at the time
    • Which cofactors are required for SOX2 to maintain vs. initially open chromatin sites is not resolved
    • Whether continuous SOX2 requirement is universal or cell-type-specific was not fully tested
  14. 2024 High

    Integrative structural biology showed that SOX2's C-terminal IDR undergoes large conformational rearrangements upon DNA and nucleosome binding, variably exposing two activation domains — providing a structural rationale for context-dependent transcriptional output.

    Evidence Single-molecule FRET, NMR spectroscopy, and molecular dynamics simulations

    PMID:38365983

    Open questions at the time
    • How specific partner factors (OCT4, p63) influence IDR conformation was not tested
    • Whether IDR conformational states correlate with pioneer vs. non-pioneer binding events is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how SOX2's RNA-binding and condensate-forming activities integrate with its pioneer transcription factor function in vivo, and how the multiple phosphorylation and ubiquitination inputs are coordinated to achieve precise SOX2 dosage in specific developmental and oncogenic contexts.
  • No integrated model connects phase separation, RNA binding, and chromatin opening in a physiological setting
  • Cross-talk between phosphorylation (CDK1/CDK2/AKT) and ubiquitin ligase/DUB pairs has not been mapped
  • Structural basis of SOX2 partner switching (OCT4 → p63 → PAX6) is not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 9 GO:0003677 DNA binding 8 GO:0003723 RNA binding 1 GO:0042393 histone binding 1
Localization
GO:0005634 nucleus 5 GO:0005694 chromosome 4
Pathway
R-HSA-74160 Gene expression (Transcription) 7 R-HSA-4839726 Chromatin organization 5 R-HSA-162582 Signal Transduction 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-1266738 Developmental Biology 3
Partners
COP1OTUD7BPAX6POU2F1POU5F1TP63TRIM26WWP2
Complex memberships
CUL4A–DET1–COP1 E3 ligase complex (as substrate)SOX2–OCT4 heterodimerSOX2–p63 complex

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 Cryo-electron microscopy structures of the SOX2 HMG DNA-binding domain bound to nucleosomes show that SOX2 binds and locally distorts nucleosomal DNA at superhelical location 2, facilitates detachment of terminal nucleosomal DNA from the histone octamer to increase DNA accessibility, and repositions the N-terminal tail of histone H4 (including K16), suggesting incompatibility with higher-order nucleosome stacking — thus mechanistically explaining SOX2 pioneer factor activity in chromatin opening. Cryo-electron microscopy structure determination Nature High 32350470
2020 Cryo-EM structures of OCT4-SOX2 bound to nucleosomes at two preferred positions show that OCT4-SOX2 differentially distort nucleosomal DNA depending on motif location; at one position they remove DNA from histones H2A and H3, while at an inverted motif only local DNA distortions occur. OCT4 uses only one of its two DNA-binding domains in both structures. Cryo-electron microscopy structure determination; in vitro binding mapping at base-pair resolution Science High 32327602
2020 Human SOX2 directly binds RNA through its HMG DNA-binding domain in vitro, interacting primarily with double-stranded RNA in a non-sequence-specific fashion via a similar but not identical surface to that used for DNA binding. UV-crosslink immunoprecipitation in mouse ESCs identified over a thousand SOX2-RNA interactions in vivo. In vitro binding assay; UV-crosslinked immunoprecipitation (fRIP-seq) in mouse ESCs Nature Communications High 32286318
2006 Sox2 overexpression in neural progenitors upregulates Notch1, RBP-J, and Hes5 transcripts, acting upstream of the Notch signaling pathway to maintain progenitor proliferation and inhibit neurogenesis; the Sox2 HMG domain alone is sufficient to confer these effects. Overexpression of constitutively active Sox2 and dominant-negative HMG domain constructs in neural progenitor cells; Notch pathway inhibition rescue experiments Developmental Biology Medium 16631155
2006 Sox2 forms a complex with Oct-1 (Pou2f1) to cooperatively bind DNA and transactivate the Pax6 lens ectoderm enhancer; specific Sox- and Octamer-binding sites are required for this cooperative complex formation and are essential for Pax6 enhancer activity in the lens placode in vivo. In vitro transactivation assay; cooperative DNA binding assay; transgenic mouse embryo enhancer analysis; genetic combination of Sox2 and Pou2f1 mutant alleles Developmental Biology High 17140559
2007 SOX2 and PAX6 cooperatively bind a 36-bp minimal core sequence of the Sox2 N-3 enhancer (containing a SOX-binding sequence and a non-canonical PAX6 paired-domain binding sequence) and synergistically activate it in transfected cells; this cooperative binding occurs with a higher threshold of factor levels than previously characterized enhancer DC5. Enhancer deletion/mutagenesis; transfection-based transactivation assay; DNA-protein binding assay Genes to Cells Medium 17825048
2014 In squamous cell carcinomas, SOX2 preferentially interacts with the transcription factor p63 (rather than OCT4 as in ES cells) at thousands of co-occupied genomic loci; SOX2 and p63 jointly regulate gene expression including the oncogene ETV4, which is essential for SOX2-amplified SCC cell survival. ChIP-seq; co-immunoprecipitation; siRNA knockdown with survival readout Journal of Clinical Investigation High 24590290
2015 Sox2 directly represses two Hippo pathway activators, Nf2 (Merlin) and WWC1 (Kibra), leading to exaggerated YAP function and maintenance of cancer stem cells in osteosarcomas; this Sox2-Hippo axis is conserved in glioblastomas. ChIP assay confirming direct Sox2 binding at Nf2 and WWC1 loci; siRNA knockdown; overexpression; in vivo tumorigenicity assays Nature Communications High 25832504
2018 The E3 ubiquitin ligase complex CUL4A-DET1-COP1 ubiquitylates Sox2 to promote its proteasomal degradation during neural progenitor cell differentiation, while the deubiquitylase OTUD7B removes polyubiquitin chains from Sox2 to stabilize it; COP1 acts as the substrate receptor interacting directly with Sox2. Co-immunoprecipitation; ubiquitylation assay; knockdown of COP1/OTUD7B with Sox2 protein level and NPC differentiation readout Nature Communications High 30405104
2015 Ubiquitin-conjugating enzyme Ube2s mediates K11-linked polyubiquitin chain formation at Sox2-K123, marking Sox2 for proteasomal degradation; this regulates precise Sox2 dosage in ES cells and suppresses Sox2-mediated neural ectodermal differentiation. In vitro ubiquitylation assay; site-directed mutagenesis (K123); knockdown/overexpression with ES cell self-renewal and differentiation readout Cell Death and Differentiation High 26292759
2021 TRIM26 stabilizes SOX2 protein in glioblastoma stem cells by directly binding SOX2 (via its C-terminal PRYSPRY domain, independent of its RING domain) and competitively inhibiting the interaction of SOX2 with WWP2, which is a bona fide SOX2 E3 ubiquitin ligase that polyubiquitinates and degrades SOX2. Proteomic Co-IP/MS identification; reciprocal Co-IP; ubiquitination assay; domain mutagenesis; TRIM26/WWP2 knockdown with Sox2 protein level and GSC self-renewal readout Nature Communications High 34732716
2019 USP9x is a deubiquitinase for SOX2 that directly interacts with and stabilizes SOX2 protein through removal of ubiquitin conjugates; knockdown of USP9x reduces SOX2 levels and inhibits osteosarcoma cell proliferation, which is rescued by SOX2 overexpression. Co-immunoprecipitation; deubiquitination assay; siRNA knockdown with rescue by SOX2 overexpression; in vivo xenograft Cancer Letters Medium 31605775
2024 PSMD7, a deubiquitinating enzyme, deubiquitinates and stabilizes SOX2 protein in pancreatic cancer cells, leading to activation of the Notch1 signaling pathway; restoration of SOX2 expression rescues the antitumor effects of PSMD7 knockdown. Co-immunoprecipitation; deubiquitination assay; knockdown/overexpression with Notch1 pathway and proliferation readout; SOX2 rescue experiment Cell & Bioscience Medium 38494478
2015 Cdk2 physically interacts with Sox2 and phosphorylates it at Ser-39 and Ser-253 in vitro; this phosphorylation is required for establishing the pluripotent state during reprogramming but is dispensable for ES cell self-renewal and maintenance. In vitro kinase assay; mass spectrometry identification of phosphorylation sites; site-directed mutagenesis; Co-IP; reprogramming efficiency readout Journal of Biological Chemistry High 26139602
2018 CDK1 physically interacts with Sox2 (by proteomic analysis) and phosphorylates it, promoting Sox2 nuclear localization and transcriptional activity; blockade or knockdown of CDK1 reduces Sox2 phosphorylation, nuclear localization, and transcriptional activity, and CDK1-driven tumor-initiating capacity is substantially reduced by Sox2 knockout. Proteomic interaction analysis; Co-IP; kinase-dead CDK1 mutant; Sox2 nuclear localization assay; Sox2 KO rescue experiment Cancer Research Medium 30297536
2015 AKT physically interacts with SOX2 protein and modulates its subcellular distribution; AKT kinase inhibition causes enhanced cytoplasmic retention of SOX2 (via impaired nuclear import) and successive cytoplasmic proteasomal degradation, establishing an AKT/SOX2 axis regulating breast cancer stem cell clonogenicity. Co-immunoprecipitation; subcellular fractionation; AKT kinase inhibitor treatment; nuclear transport blockade and proteasomal inhibition rescue experiments Oncotarget Medium 26498353
2017 RIT1 stimulates Akt-dependent phosphorylation of Sox2 at T118, leading to Sox2 stabilization and transcriptional activation, as part of an IGF-1-RIT1-Akt-Sox2 signaling cascade that promotes hippocampal neurogenesis; RIT1 knockout blunts IGF-1-dependent Sox2 stabilization and neuronal differentiation. Phosphorylation assay identifying T118 site; RIT1 knockout mouse; in vivo IGF-1 infusion; neural progenitor proliferation/differentiation readout Scientific Reports Medium 28607354
2012 SUMOylation of Sox2 by Pias3 inhibits Nanog expression and impairs the interaction between Sox2 and Oct4; conversely, SUMOylation of Oct4 by Pias2 enhances Nanog expression, indicating that SUMO modifications on Sox2 and Oct4 have opposing regulatory effects on the Sox2-Oct4 heterodimer and downstream targets. Co-immunoprecipitation; SUMO pathway manipulation (Ubc9/Sumo1 depletion); Nanog luciferase reporter assay PLoS ONE Medium 22745796
2011 SOX2 knockdown in melanoma cells results in 4.5-fold decreased invasiveness, while SOX2 overexpression increases invasiveness 3.8-fold; SOX2 knockdown reduces MMP-3 mRNA by 87.8%, and MMP-3 knockdown similarly inhibits invasion, placing MMP-3 as a downstream mediator of SOX2-driven melanoma invasion. siRNA knockdown; SOX2 overexpression; in vitro invasion assay; RT-PCR screening of 84 invasion-related genes; MMP-3 KD epistasis Laboratory Investigation Medium 22184093
2014 SOX2 targets Src kinase in ovarian cancer cells to promote cell migration and invasion; SOX2 overexpression activates Src kinase, and Src is identified as a key downstream mediator of SOX2-driven migration and invasion. SOX2 overexpression and knockdown; cell migration/invasion assay; Src kinase activity measurement PLoS ONE Low 24937695
2011 SOX2 interacts with heterogeneous nuclear ribonucleoprotein (hnRNP) family members (HNRNPA2B1, HNRNPA3, HNRNPC, HNRNPK, HNRNPL, HNRNPM, HNRNPR, HNRNPU) and other ribonucleoproteins, as identified by immunoprecipitation/MS in glioblastoma cells, suggesting a role for SOX2 in post-transcriptional regulation. Immunoprecipitation followed by tandem mass spectrometry (IP/MS/MS) Proteomics Low 21280222
2017 OCT4 and SOX2 function as transcriptional activators during reprogramming of human fibroblasts: replacing SOX2 with SOX2-VP16 (strong activator) increased reprogramming efficiency, while SOX2-HP1 (strong repressor) eliminated reprogramming; at early reprogramming stages, DNA-bound SOX2 is embedded in putative enhancers, about half of which are created de novo. Substitution of SOX2 with activation/repression domain fusion proteins; reprogramming efficiency assay; ChIP-seq Cell Reports Medium 28813671
2020 Sox2 interacts with the RNA helicase Ddx5 and inhibits its resolvase activity on R-loops, thereby facilitating somatic cell reprogramming to pluripotency; Sox2 is the only Yamanaka factor whose overexpression overcomes reprogramming blockade caused by RNaseH1 loss. Co-immunoprecipitation; R-loop profiling (DRIP-seq); RNaseH1 catalytic mutant; reprogramming efficiency assay; epistasis (Sox2 vs. other OSKM factors) Science Advances Medium 32704541
2016 SOX2 directly binds the EPCAM promoter and induces EpCAM-p21Cip1-cyclin A2 signaling to encourage lung cancer cell proliferation; additionally, SOX2 suppresses SOX9 expression by increasing H3K9me2 levels on the SOX9 promoter, with SOX9 driving invasive/spindle-like behavior. ChIP assay; promoter reporter assay; SOX2/SOX9 overexpression and knockdown; HDAC inhibitor treatment Cancer Research Medium 27758880
2016 SOX2 binds the HHAT promoter (as shown by ChIP-PCR and luciferase reporter assay) to activate Hedgehog signaling, mediating radioresistance in cervical cancer cells. Luciferase reporter assay; ChIP-PCR; radioresistant cell line model; SOX2 knockdown/overexpression with clonogenic survival readout Gynecologic Oncology Medium 30336948
2016 SOX2 directly suppresses CDKN1A (p21) expression in lung squamous cell carcinoma, and G1 cell cycle arrest induced by SOX2 siRNA is rescued by simultaneous CDKN1A siRNA knockdown, demonstrating functional epistasis. RNA-seq correlation analysis; siRNA knockdown; genetic epistasis (double knockdown rescue of cell cycle arrest) Scientific Reports Medium 26846300
2014 SOX2 directly binds the Lef-1 promoter at a functional Sox2 DNA-binding site (demonstrated by transcriptional reporter assays, ChIP, and DNA-protein binding studies) and represses Wnt/β-catenin-dependent Lef-1 transcription in airway epithelium, with Sox2 conditional deletion enhancing Lef-1 expression. Transcriptional reporter assay; ChIP; DNA-protein binding assay; conditional Sox2 deletion in primary airway epithelium American Journal of Physiology: Lung Cellular and Molecular Physiology Medium 24487391
2022 SOX2 forms co-condensates with DNA and generates mechanical forces up to 7 pN via its disordered domains (which are required for maximum force generation but not condensate formation); nucleosomes attenuate this mechanical stress by sequestering SOX2 from coalescing on bare DNA. Single-molecule force spectroscopy; FRET; condensate assay with SOX2 domain mutants; nucleosome binding experiments Nature Communications High 35810158
2024 NMR spectroscopy and single-molecule FRET integrated with molecular simulations show that the C-terminal intrinsically disordered region (IDR) of SOX2 is highly disordered but guided by weak charge interactions with the folded HMG domain; DNA and nucleosome binding induce major rearrangements in the IDR ensemble, redistributing interdomain interactions and variably exposing two activation domains critical for transcription. Single-molecule FRET; NMR spectroscopy; molecular dynamics simulations Nature Communications High 38365983
2023 Acute depletion of SOX2 in mESCs causes rapid loss of thousands of accessible chromatin sites within one hour, demonstrating SOX2 pioneer activity is required for dynamic maintenance of open chromatin; SOX2-maintained open chromatin sites are highly predictive of gene expression, while other SOX2 binding sites are largely dispensable for transcription. Acute protein depletion (auxin-inducible degron); ATAC-seq; nascent transcription analysis; CRISPR-Cas9 validation of regulatory element EMBO Journal High 37691488
2023 At the endogenous Sox2 locus in mESCs, two DNase I hypersensitive sites (DHSs) are each individually sufficient for long-range Sox2 activation through key transcription factor recognition sequences, while three nearby DHSs show no independent activity but dramatically augment the autonomous DHSs in a context-dependent manner. Large-scale synthetic regulatory genomics (Big-IN scarless integration); DHS deletion/rearrangement/inversion; TF motif mutagenesis; Sox2 expression quantification in multiple mESC clones Molecular Cell High 36931273
2023 SOX2 occupies preaccessible enhancers in E3.5 ICM (partly opened by early-stage TFs TFAP2C and NR5A2) and widely redistributes upon naive and formative pluripotency transitions, either opening enhancers or poising them for rapid future activation, revealing a multifaceted and stage-dependent pioneer factor function in vivo. CUT&RUN/ChIP-seq of SOX2 binding in mouse embryos from E3.5–E7.5; chromatin accessibility profiling; genetic loss-of-function Science High 38096290
2021 SOX2 reprogramming of the esophageal epigenome involves: (1) acquiring new binding sites with Klf5 at oncogenes such as Stat3, (2) activating endogenous retroviruses inducing double-stranded RNA expression, and (3) creating dependence on the RNA editing enzyme ADAR1, revealing that oncogenic Sox2 cistrome evolution drives new targetable vulnerabilities. Murine esophageal organoids (normal to SCC progression); Sox2 ChIP-seq; ATAC-seq; transcriptome analysis; ADAR1 functional dependence assay Nature Genetics High 33972779
2020 TRIM24 activates Sox2 expression in glioblastoma stem cells by directly binding the Sox2 promoter (demonstrated by ChIP and reporter gene assay), thereby regulating GBM stemness and invasiveness. ChIP assay; reporter gene assay; TRIM24 knockdown with Sox2 expression and GSC self-renewal readout; xenograft Neuro-oncology Medium 32492707
2019 Sox2 interacts with JMJD5 (a direct transcriptional target of Sox2 in cerebral endothelial cells) to induce endothelial-mesenchymal transition (EndMT) in cerebral arteriovenous malformations; endothelial-specific Sox2 suppression normalizes endothelial differentiation and lumen formation. Epigenetic profiling; Co-IP; EC-specific Sox2 conditional knockout mouse; lumen formation assay Journal of Clinical Investigation Medium 31232700
2020 Sox2 directly controls fibronectin fibrillogenesis in Schwann cells by upregulating extracellular matrix and migration genes and promoting focal adhesion formation, providing an oriented fibronectin matrix required for Schwann cell directional migration and neuron guidance along Schwann cells. Sox2 overexpression/knockdown in Schwann cell line; fibronectin fibrillogenesis assay; focal adhesion immunostaining; directional migration assay; neuron co-culture; in vivo sciatic nerve regeneration model Scientific Reports Medium 32029747

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Mutations in SOX2 cause anophthalmia. Nature genetics 422 12612584
2019 SOX2 in development and cancer biology. Seminars in cancer biology 277 31412296
2006 Role of Sox2 in the development of the mouse neocortex. Developmental biology 234 16631155
2014 SOX2 and cancer: current research and its implications in the clinic. Clinical and translational medicine 218 25114775
2013 The multiple roles for Sox2 in stem cell maintenance and tumorigenesis. Cellular signalling 214 23416461
2015 Sox2 antagonizes the Hippo pathway to maintain stemness in cancer cells. Nature communications 206 25832504
2020 Nucleosome-bound SOX2 and SOX11 structures elucidate pioneer factor function. Nature 202 32350470
2020 Mechanisms of OCT4-SOX2 motif readout on nucleosomes. Science (New York, N.Y.) 184 32327602
2017 The dark side of SOX2: cancer - a comprehensive overview. Oncotarget 176 28388544
2020 Functional characterization of SOX2 as an anticancer target. Signal transduction and targeted therapy 168 32728033
2011 MicroRNA-126 inhibits SOX2 expression and contributes to gastric carcinogenesis. PloS one 148 21304604
2014 SOX2 and p63 colocalize at genetic loci in squamous cell carcinomas. The Journal of clinical investigation 147 24590290
2007 Expression of LHX3 and SOX2 during mouse inner ear development. Gene expression patterns : GEP 132 17604700
2016 Yin Yang 1 is associated with cancer stem cell transcription factors (SOX2, OCT4, BMI1) and clinical implication. Journal of experimental & clinical cancer research : CR 123 27225481
2018 CDK1 Interacts with Sox2 and Promotes Tumor Initiation in Human Melanoma. Cancer research 105 30297536
2010 Expression of pax6 and sox2 in adult olfactory epithelium. The Journal of comparative neurology 102 20852734
2010 Sox2 activates cell proliferation and differentiation in the respiratory epithelium. American journal of respiratory cell and molecular biology 101 20855650
2006 Sox2 and Pou2f1 interact to control lens and olfactory placode development. Developmental biology 94 17140559
2011 SOX2 contributes to melanoma cell invasion. Laboratory investigation; a journal of technical methods and pathology 92 22184093
2017 Colitis promotes neuronal differentiation of Sox2+ and PLP1+ enteric cells. Scientific reports 90 28566702
2014 Sox2 expression involvement in the oncogenicity and radiochemoresistance of oral cancer stem cells. Oral oncology 90 25456004
2020 The Sox2 transcription factor binds RNA. Nature communications 86 32286318
2017 IGF-1 mediated Neurogenesis Involves a Novel RIT1/Akt/Sox2 Cascade. Scientific reports 82 28607354
2017 SOX2 regulates acinar cell development in the salivary gland. eLife 79 28623666
2015 Overview of the roles of Sox2 in stem cell and development. Biological chemistry 78 25781683
2021 Reprogramming of the esophageal squamous carcinoma epigenome by SOX2 promotes ADAR1 dependence. Nature genetics 77 33972779
2007 PAX6 and SOX2-dependent regulation of the Sox2 enhancer N-3 involved in embryonic visual system development. Genes to cells : devoted to molecular & cellular mechanisms 75 17825048
2018 miR-145-5p Suppresses Breast Cancer Progression by Inhibiting SOX2. The Journal of surgical research 72 30694767
2008 Sox2 expression in brain tumors: a reflection of the neuroglial differentiation pathway. The American journal of surgical pathology 70 18162777
2018 Targeting SOX2 in anticancer therapy. Expert opinion on therapeutic targets 66 30366514
2019 Age-related transcriptome changes in Sox2+ supporting cells in the mouse cochlea. Stem cell research & therapy 65 31791390
2019 Endogenous fluctuations of OCT4 and SOX2 bias pluripotent cell fate decisions. Molecular systems biology 61 31556488
2018 Sox2 haploinsufficiency primes regeneration and Wnt responsiveness in the mouse cochlea. The Journal of clinical investigation 61 29553487
2018 LncRNA SNHG5/miR-26a/SOX2 signal axis enhances proliferation of chondrocyte in osteoarthritis. Acta biochimica et biophysica Sinica 59 29409014
2018 Dynamic ubiquitylation of Sox2 regulates proteostasis and governs neural progenitor cell differentiation. Nature communications 57 30405104
2011 Landscape of the SOX2 protein-protein interactome. Proteomics 57 21280222
2010 ChIP-seq and functional analysis of the SOX2 gene in colorectal cancers. Omics : a journal of integrative biology 57 20726797
2016 Epigenetic Switch between SOX2 and SOX9 Regulates Cancer Cell Plasticity. Cancer research 55 27758880
2020 R-loops coordinate with SOX2 in regulating reprogramming to pluripotency. Science advances 53 32704541
2014 Functional characterization of SOX2 in bovine preimplantation embryos. Biology of reproduction 52 24389873
2021 Competitive binding of E3 ligases TRIM26 and WWP2 controls SOX2 in glioblastoma. Nature communications 51 34732716
2015 Ube2s regulates Sox2 stability and mouse ES cell maintenance. Cell death and differentiation 48 26292759
2023 Synthetic regulatory genomics uncovers enhancer context dependence at the Sox2 locus. Molecular cell 47 36931273
2014 SOX2 enhances the migration and invasion of ovarian cancer cells via Src kinase. PloS one 47 24937695
2019 Sox2: A Regulatory Factor in Tumorigenesis and Metastasis. Current protein & peptide science 46 30907312
2014 Sox2 regulates cholinergic amacrine cell positioning and dendritic stratification in the retina. The Journal of neuroscience : the official journal of the Society for Neuroscience 43 25057212
2012 SUMOylation represses Nanog expression via modulating transcription factors Oct4 and Sox2. PloS one 43 22745796
2022 Chromatin sequesters pioneer transcription factor Sox2 from exerting force on DNA. Nature communications 41 35810158
2020 An FGFR/AKT/SOX2 Signaling Axis Controls Pancreatic Cancer Stemness. Frontiers in cell and developmental biology 41 32457900
2018 SOX2 regulates radioresistance in cervical cancer via the hedgehog signaling pathway. Gynecologic oncology 40 30336948
2016 Paradoxical role of SOX2 in gastric cancer. American journal of cancer research 40 27186426
2010 Forced expression of Sox21 inhibits Sox2 and induces apoptosis in human glioma cells. International journal of cancer 40 20824710
2020 TRIM24 promotes stemness and invasiveness of glioblastoma cells via activating Sox2 expression. Neuro-oncology 39 32492707
2016 SOX2 suppresses CDKN1A to sustain growth of lung squamous cell carcinoma. Scientific reports 39 26846300
2015 Cyclin-dependent kinase-mediated Sox2 phosphorylation enhances the ability of Sox2 to establish the pluripotent state. The Journal of biological chemistry 39 26139602
2015 Molecular and functional interactions between AKT and SOX2 in breast carcinoma. Oncotarget 38 26498353
2016 Sox2: regulation of expression and contribution to brain tumors. CNS oncology 36 27230973
2020 Sox2 controls Schwann cell self-organization through fibronectin fibrillogenesis. Scientific reports 35 32029747
2019 Elevated endothelial Sox2 causes lumen disruption and cerebral arteriovenous malformations. The Journal of clinical investigation 35 31232700
2012 Cellular reprogramming employing recombinant sox2 protein. Stem cells international 35 22693519
2022 Deconstructing Sox2 Function in Brain Development and Disease. Cells 34 35626641
2019 Targeting USP9x/SOX2 axis contributes to the anti-osteosarcoma effect of neogambogic acid. Cancer letters 34 31605775
2012 Sox2 regulation of hair cell development: incoherence makes sense. Hearing research 34 23154195
2017 OCT4 and SOX2 Work as Transcriptional Activators in Reprogramming Human Fibroblasts. Cell reports 33 28813671
2008 Hypermethylation of SOX2 gene in hydatidiform mole and choriocarcinoma. Reproductive sciences (Thousand Oaks, Calif.) 33 18836133
2023 Multifaceted SOX2-chromatin interaction underpins pluripotency progression in early embryos. Science (New York, N.Y.) 32 38096290
2013 Clinicopathologic implications of EpCAM and Sox2 expression in breast cancer. Clinical breast cancer 32 24201161
2007 Expression of Sox2 in mature and immature teratomas of central nervous system. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 32 17464316
2008 Expression of Sox2 in mouse taste buds and its relation to innervation. Cell and tissue research 31 18379823
2008 Expression of Sox1, Sox2 and Sox9 is maintained in adult human cerebellar cortex. Neuroscience letters 30 19061938
2017 Sox2 is dispensable for primary melanoma and metastasis formation. Oncogene 28 28368416
2012 Oct4 and Sox2 are overexpressed in human neuroblastoma and inhibited by chemotherapy. Oncology reports 28 22576801
2014 Clinicopathologic significance of Sox2, CD44 and CD44v6 expression in intrahepatic cholangiocarcinoma. Pathology oncology research : POR 27 24482053
2021 SOX21 modulates SOX2-initiated differentiation of epithelial cells in the extrapulmonary airways. eLife 26 34286693
2020 SOX2 and squamous cancers. Seminars in cancer biology 26 32905832
2018 SOX2 expression diminishes with ageing in several tissues in mice and humans. Mechanisms of ageing and development 25 29574045
2024 Deubiquitinase PSMD7 facilitates pancreatic cancer progression through activating Nocth1 pathway via modifying SOX2 degradation. Cell & bioscience 24 38494478
2023 Reciprocal regulation of LINC00941 and SOX2 promotes progression of esophageal squamous cell carcinoma. Cell death & disease 24 36717549
2020 Critical role of SOX2-IGF2 signaling in aggressiveness of bladder cancer. Scientific reports 24 32427884
2023 LncRNA GSCAR promotes glioma stem cell maintenance via stabilizing SOX2 expression. International journal of biological sciences 23 37063420
2021 MicroRNAs regulating SOX2 in cancer progression and therapy response. Expert reviews in molecular medicine 23 34583803
2018 Crosstalk between SOX2 and cytokine signaling in endometrial carcinoma. Scientific reports 23 30510261
2017 Sox2 regulates astrocytic and vascular development in the retina. Glia 23 29178409
2024 DNA binding redistributes activation domain ensemble and accessibility in pioneer factor Sox2. Nature communications 22 38365983
2022 SOX2 transcription factor binding and function. Development (Cambridge, England) 22 35861233
2019 Sox2 dosage: A critical determinant in the functions of Sox2 in both normal and tumor cells. Journal of cellular physiology 22 31344986
2023 Pioneer activity distinguishes activating from non-activating SOX2 binding sites. The EMBO journal 21 37691488
2020 circ_0005273 promotes thyroid carcinoma progression by SOX2 expression. Endocrine-related cancer 21 31693489
2019 SIX1 represses senescence and promotes SOX2-mediated cellular plasticity during tumorigenesis. Scientific reports 21 30723235
2014 Sox2 modulates Lef-1 expression during airway submucosal gland development. American journal of physiology. Lung cellular and molecular physiology 21 24487391
2018 Sodium selenite attenuates lung adenocarcinoma progression by repressing SOX2-mediated stemness. Cancer chemotherapy and pharmacology 20 29546459
2017 SOX2-silenced squamous cell carcinoma: a highly malignant form of esophageal cancer with SOX2 promoter hypermethylation. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 20 28862264
2014 Expression of Sox2 in cervical squamous cell carcinoma. Journal of B.U.ON. : official journal of the Balkan Union of Oncology 20 24659665
2021 DYRK1A Negatively Regulates CDK5-SOX2 Pathway and Self-Renewal of Glioblastoma Stem Cells. International journal of molecular sciences 19 33924599
2019 SOX2 antagonizes WWC1 to drive YAP1 activation in esophageal squamous cell carcinoma. Cancer medicine 18 31560173
2014 Neuronal expression of SOX2 is enriched in specific hypothalamic cell groups. Journal of chemical neuroanatomy 18 25263324
2021 Heparanase 2 (Hpa2) attenuates tumor growth by inducing Sox2 expression. Matrix biology : journal of the International Society for Matrix Biology 17 34004353
2019 Glioma SOX2 expression decreased after adjuvant therapy. BMC cancer 17 31718604
2016 Sox2: To crest or not to crest? Seminars in cell & developmental biology 17 27592260
2010 Candidate gene sequencing of LHX2, HESX1, and SOX2 in a large schizencephaly cohort. American journal of medical genetics. Part A 17 20949537