Fact-checked by Grok 2 weeks ago

SOX2

SOX2 is an intronless on human chromosome 3q26.33 that encodes a belonging to the SRY-related HMG-box (SOX) family, characterized by a conserved high-mobility-group (HMG) . This protein functions primarily as a transcriptional regulator, binding to specific DNA sequences to activate or repress target , often in partnership with cofactors like OCT4 and Nanog, thereby playing a pivotal role in embryonic development, pluripotency, and cell fate decisions. Mutations in SOX2 are linked to developmental disorders such as , , and , highlighting its indispensable function in ocular and neural formation. In embryonic stem cells, SOX2 is a core component of the pluripotency network, maintaining self-renewal and inhibiting by directly regulating genes involved in and lineage commitment. It is essential from the early embryonic stages, such as the 2-cell stage in mice, and its absence leads to peri-implantation lethality due to failure in forming the . Beyond pluripotency, SOX2 governs the development of multiple lineages, including by antagonizing mesendoderm fate, retinal progenitors through Notch1 activation, and endoderm-derived structures like the and forestomach, where graded expression levels dictate tissue specification. In adult tissues, SOX2 sustains populations in neural, epithelial, and mesenchymal compartments, and its ectopic expression, alongside OCT4, , and c-MYC, enables the reprogramming of somatic cells into induced pluripotent stem cells. Dysregulation of SOX2 contributes significantly to oncogenesis, where it acts as an in various malignancies by enhancing cancer properties, epithelial-mesenchymal transition, , and therapeutic resistance. or overexpression is frequently observed in squamous cell carcinomas of the , , and head and , as well as and , correlating with poor prognosis in many cases. Post-translational modifications, including by AKT at Thr118 (mouse)/Thr116 (human), at Lys75, and ubiquitination at Lys115, modulate SOX2 stability, localization, and activity, often linking it to oncogenic pathways like PI3K/AKT. These multifaceted roles underscore SOX2's position as a key molecular switch in both normal development and pathological states.

Gene and Protein Structure

Genomic Location and Organization

The SOX2 gene was first identified in 1994 through screening human cDNA libraries for sequences homologous to the SRY gene, establishing it as a founding member of the SOX family of transcription factors. In humans, SOX2 is located on the long arm of at the 3q26.33 cytogenetic band, spanning genomic coordinates 181,711,925 to 181,714,436 (GRCh38.p14 assembly), encompassing approximately 2.5 kb. The orthologous mouse Sox2 gene resides on at position 34,704,144–34,706,610 (GRCm39 assembly), also spanning about 2.5 kb. The structure of SOX2 is notably simple, consisting of a single without , a feature unique among many SOX family members and encoding the full 3' untranslated region, coding sequence, and within this compact unit. This intronless organization places SOX2 entirely within the third of the overlapping SOX2OT, which is transcribed in the same orientation and may influence its regulation. Key regulatory elements include a proximal promoter and multiple distal enhancers, such as the Sox2 regulatory regions 1 and 2 (SRR1 and SRR2), which drive tissue-specific expression during development. Evolutionarily, SOX2 exhibits strong conservation across vertebrate species, reflecting its essential roles in early embryogenesis, with the highest sequence homology observed in the HMG box-encoding region that facilitates DNA binding. This conservation extends to non-mammalian vertebrates like chicken and Xenopus, underscoring the gene's ancient origins within the SOX family.

Protein Domains and Function

The human SOX2 protein is a 317-amino-acid polypeptide with a calculated molecular weight of 34,310 Da. It adopts a modular characteristic of SOX family transcription factors, featuring a compact N-terminal , a central , and a disordered C-terminal extension that contributes to regulatory functions. The core DNA-binding element is the high-mobility group (HMG) box domain, spanning residues 40–111, which forms an L-shaped fold consisting of three α-helices. This domain binds sequence-specifically to DNA motifs such as CTTTGTT, inserting basic residues like arginines into the minor groove at AA/TT steps to facilitate recognition and induce sharp DNA bending of approximately 70–90 degrees, thereby altering chromatin architecture to promote access to target genes. At the C-terminus (residues approximately 180–317), SOX2 contains a transactivation domain comprising multiple subdomains (e.g., R1, R2, and R3 regions) that recruit co-activators, such as Mediator complex components, to enhance transcriptional activation. SOX2 also harbors two nuclear localization signals: a monopartite NLS near the N-terminus (residues 5–17) and a bipartite NLS C-terminal to the HMG box (residues 129–140), which mediate importin-α-dependent nuclear translocation essential for its function. Post-translational modifications further modulate SOX2 activity, with sites including Ser39 and Ser253 targeted by (CDK2), influencing protein stability and interactions, and sites like Lys75 within the HMG box affecting nuclear retention. Basic biochemical assays, including electrophoretic mobility shift assays (EMSA) and , demonstrate SOX2's high-affinity, sequence-specific DNA binding, with dissociation constants (K_d) typically in the 10–50 nM range for consensus motifs, confirming its role as a potent regulator of .

Expression Patterns

Embryonic Expression

Zygotic SOX2 expression begins at the 2-cell stage in the mouse embryo, with maternal protein present earlier, but it becomes prominently detected in the (ICM) of the at embryonic day 3.5 (E3.5), serving as a key marker alongside OCT4 and NANOG. analyses confirm SOX2 restriction to the ICM, absent from trophectoderm cells at the stage, and extending to extraembryonic ectoderm. By E4.5, as the epiblast emerges from the ICM, SOX2 transcripts are prominently detected in this pluripotent compartment, coinciding with the maintenance of naive pluripotency prior to implantation. During around E6.5–E7.5, SOX2 exhibits dynamic spatiotemporal patterns, with high expression in the epiblast, particularly in regions fated for and adjacent to the . This includes elevated levels in primitive streak progenitors and extending into the nascent . By E8.5, reveals SOX2 expression becoming restricted to the , delineating the anterior-posterior axis of the developing . Comparative studies in human embryos, leveraging single-cell RNA sequencing (scRNA-seq), mirror these patterns but on a protracted timeline. SOX2 is upregulated in the epiblast from the late blastocyst stage (Carnegie Stage 3, ~E7 in mouse equivalent), sustaining pluripotency markers through preimplantation and post-implantation stages up to Carnegie Stage 7 (~day 17). Recent scRNA-seq atlases (as of 2024) confirm enrichment in epiblast-derived neuroectoderm and primitive streak-like populations during gastrulation-equivalent phases (Carnegie Stages 7–8), with progressive restriction to neural lineages by early organogenesis.

Adult Tissue Expression

In adult mammals, SOX2 maintains persistent expression in neural stem cells (NSCs) within specific niches, including the (SVZ) along the lateral ventricle and the subgranular zone (SGZ) of the . In these regions, SOX2-positive cells exhibit multipotency, generating neurons, , and , as demonstrated by fate mapping using lentiviral and retroviral tracing in transgenic mice expressing SOX2-GFP. (IHC) reveals SOX2 nuclear localization in radial glia-like NSCs marked by GFAP and Nestin, with approximately 10% of progeny retaining SOX2 expression to support self-renewal. Single-cell RNA sequencing (scRNA-seq) of human SVZ tissues confirms SOX2 enrichment in quiescent and activated NSCs, underscoring its role in homeostasis. SOX2 shows low-level expression in stem and compartments of select adult epithelial tissues, such as the and basal , , and gastrointestinal () tract. In the cornea, IHC detects SOX2 in the nuclei of limbal cells co-expressing p63, but it is absent in suprabasal differentiated layers, with RT-PCR and showing reduced SOX2 mRNA during of limbal epithelial cells. Similarly, in the adult , SOX2 marks putative cells at the that contribute to secondary fiber formation throughout life, as identified by lineage tracing and IHC in mice. In the tract, particularly the glandular , SOX2 is expressed at low levels in basal / cells maintaining epithelial renewal, with scRNA-seq highlighting its presence in Lgr5-negative populations. SOX2 expression is dynamically induced in response to tissue injury to promote regeneration in neural and retinal contexts. Following retinal damage in zebrafish, Sox2 mRNA and protein levels surge in Müller glia within 31 hours, driving their reprogramming into proliferative neuronal progenitors essential for photoreceptor replacement, as shown by morpholino knockdown experiments. In mammalian auditory nerve injury, IHC reveals Sox2 upregulation in supporting cells and glia, correlating with increased proliferation. Human and mouse RNA-seq datasets from injured neural tissues further support this induction, contrasting with baseline quiescence. In differentiated lineages, such as hepatocytes and cardiomyocytes, SOX2 is absent or silenced, with GTEx RNA-seq data indicating negligible expression in liver and heart tissues, reflecting its restriction to undifferentiated stem states.

Regulation

Transcriptional Regulation

The transcription of the SOX2 gene is tightly controlled by a core regulatory network in pluripotent cells, where SOX2, OCT4, and NANOG form interconnected autoregulatory and feed-forward loops. These factors bind to shared enhancer elements and promoters, including their own, to maintain self-renewal and prevent ; for instance, SOX2 and OCT4 co-occupy composite DNA motifs within the Nanog proximal promoter, facilitating chromatin looping that stabilizes the pluripotency circuitry. This auto-regulation is evident in and embryonic stem cells (ESCs), where mutual binding enhances transcriptional activation and resilience to external signals. In ESCs, the LIF/STAT3 signaling pathway activates SOX2 transcription to sustain pluripotency. LIF binding to its receptor triggers JAK-mediated of STAT3, which translocates to the and directly binds STAT consensus motifs in the SOX2 promoter, initiating SOX2 expression and reinforcing the core network through upstream factors like KLF4. This pathway shields SOX2 from repressive ERK signaling, ensuring stable expression during ground-state maintenance. Conversely, during , FGF and WNT pathways repress SOX2 to promote ; in neuro-mesodermal progenitors, WNT-activated Brachyury (T) cooperates with β-catenin to bind and repress SOX2-occupied neural enhancers, shifting cells toward while downregulating SOX2 levels. FGF signaling similarly attenuates SOX2 in exiting ESCs by activating ERK, which disrupts the pluripotency loop and favors neuroectodermal or mesodermal fates. Thyroid hormone (T3) provides context-specific repression of SOX2, particularly in neural contexts, by acting through thyroid hormone receptor α1 (TRα1). T3-bound TRα1 directly interacts with two negative thyroid hormone response elements (TREs) in the SOX2 regulatory region 1 (SRR1) promoter, recruiting corepressors to silence transcription and promote progression from neural stem cells to migrating neuroblasts. This mechanism is critical in the adult , where T3 elevation accelerates neuronal by curtailing SOX2-mediated progenitor maintenance. Neural-specific SOX2 expression relies on dedicated enhancer clusters, such as the proximal SRR2 and the distal SRR2–18 complex. SRR2, located ~4 kb downstream of the SOX2 , drives expression in multipotent neural progenitors within the embryonic ventricular zone, independent of activity. The SRR2–18 cluster, spanning multiple conserved elements, forms loops with the SOX2 promoter in neural stem/progenitor cells derived from ESCs, ensuring region-specific dosage control and precise regulation of anterior-posterior neural fates during . ChIP-seq analyses have validated key binding motifs within SOX2 regulatory regions, highlighting context-dependent control. For example, in , PAX6 binds composite motifs in SOX2 enhancers alongside SOX2 itself, co-regulating lens-specific genes and modulating SOX2 activity in neuroectodermal progenitors; such sites exhibit cooperative enrichment, with PAX6 promoting SOX2-dependent neuronal specification. These motifs, often paired with SOX or PAX consensus sequences, enable fine-tuned activation in ocular lineages.

Post-transcriptional and Epigenetic Regulation

Post-transcriptional regulation of SOX2 primarily occurs through microRNA-mediated repression and modulation of mRNA stability via 3' untranslated region (3' UTR) elements. In human embryonic stem cells (hESCs), miR-145 directly targets the 3' UTR of SOX2 mRNA, suppressing its translation and promoting by disrupting the pluripotency that includes OCT4 and KLF4. Similarly, the let-7 family of microRNAs, particularly let-7i, represses SOX2 expression indirectly by inhibiting LIN28, which normally blocks let-7 biogenesis; this pathway limits SOX2 levels in neural precursors, thereby facilitating and restricting proliferation. Post-transcriptional control is dominated by 3' UTR interactions that affect mRNA stability. The RBM24 binds AU-rich elements in the SOX2 3' UTR, stabilizing the transcript and ensuring adequate SOX2 protein levels during vertebrate ; disruption of this binding reduces mRNA half-life and leads to ocular malformations. Epigenetic mechanisms further fine-tune SOX2 expression through chromatin modifications that influence accessibility and transcriptional competence. In pluripotent stem cells, the SOX2 promoter is marked by activating histone modifications, which maintain an open state permissive for SOX2 transcription and self-renewal. Conversely, repressive marks accumulate at the SOX2 locus during lineage commitment, silencing expression to prevent ectopic pluripotency maintenance. The polycomb repressive complex 2 (PRC2) drives this deposition, particularly during , where its activity represses SOX2 and other core pluripotency factors to enable proper specification and embryonic patterning; PRC2 deficiency results in sustained SOX2 expression and defective toward meso-endoderm lineages.

Biological Roles

In Pluripotency and Stem Cells

SOX2 plays a central role in maintaining pluripotency and self-renewal in embryonic cells (ESCs) by forming a core transcriptional regulatory triad with OCT4 and NANOG. This triad binds cooperatively to composite enhancer elements containing SOX/POU motifs, activating the expression of key pluripotency genes such as Rex1 (also known as Zfp42) and Utf1. These interactions ensure the stable propagation of the undifferentiated state in both and ESCs. In induced pluripotent stem cells (iPSCs), SOX2 is one of the four Yamanaka factors (along with OCT4, , and c-MYC) required to dedifferentiate cells into a pluripotent state. The dosage of SOX2 significantly influences efficiency; low SOX2 levels can enhance the generation of partially reprogrammed iPSCs when combined with other factors, while optimal stoichiometric ratios are critical for full , as deviations in SOX2 expression relative to OCT4 can either boost or impair the process. Within ESCs, SOX2 promotes symmetric cell division to support population expansion and self-renewal by regulating cell cycle genes, including cyclin-dependent kinases. Upon receiving differentiation cues, such as altered signaling from FGF4 or other extrinsic factors, SOX2 expression diminishes, facilitating the exit from pluripotency and progression toward lineage commitment. Genetic assays underscore SOX2's indispensability: homozygous SOX2 knockout in mice results in embryonic lethality shortly after blastocyst implantation due to failure in epiblast formation and maintenance of pluripotency. Rescue experiments demonstrate that forced expression of OCT4 in SOX2-null ESCs can restore pluripotency markers and self-renewal capacity, highlighting the interconnected nature of the core triad. Recent advances have revealed enhanced cooperativity between SOX2 and OCT4 in establishing the pluripotency during early embryogenesis, where they co-occupy enhancers to activate pluripotency-related genes through OCT-SOX motifs. Additionally, heterogeneous transcriptional dynamics of SOX2 in ESCs contribute to variable exit thresholds from pluripotency, providing quantitative insights into how fluctuations in SOX2 levels influence differentiation propensity.

In Neural Development

SOX2 plays a critical role in maintaining neural stem cells (NSCs) within the ventricular zone of the developing and adult brain, where it regulates proliferation by modulating progression. In these progenitors, SOX2 interacts with transcription factors such as Ascl1 to balance self-renewal and , ensuring sustained NSC pools during . Specifically, SOX2 forms a transcriptional network that acts as a molecular switch, promoting the expression of genes like Ascl1 to control entry into the and prevent premature in the . Recent studies have elucidated SOX2's involvement in distinct modes of , particularly in basal radial glia (bRG) of the outer . While traditional models emphasized indirect through intermediate , SOX2-expressing bRG undergo frequent symmetric amplifying divisions to expand the pool, alongside self-consuming direct neurogenic divisions that bypass transit-amplifying cells. These 2024 findings highlight SOX2's role in amplifying numbers, contributing to cortical and production in humans. In the context of brain evolution, human-specific enhancers associated with SOX2 fine-tune radial glia potency, linking increased SOX2 activity to expansion. These enhancers, active in neural progenitors but not in other , enhance SOX2 expression in bRG and intermediate progenitors, promoting greater proliferative capacity and neuronal output that underlie the enlarged . Following brain injury, SOX2 is upregulated in reactive and gliotic regions, facilitating a stem-like response that supports repair. This upregulation promotes and potential of glial cells toward neurogenic fates during reactive . In a 2023 study, SOX2-overexpressing neural stem cells transplanted into models of posthemorrhagic reduced ventricular enlargement and improved neurological function by enhancing and integration into damaged circuits. Genetic ablation of SOX2 in mice leads to severe defects in neural development, including characterized by reduced brain size and impaired . Conditional knockouts reveal disrupted NSC maintenance in the ventricular zone, resulting in fewer neurons and progressive neurodegeneration, underscoring SOX2's essential function in progenitor survival and .

In Sensory Organ Development

SOX2 plays a critical role in the induction of the placode by cooperating with to promote al thickening and initiate lens development. In the presumptive lens , SOX2 and form a co-DNA-binding partner complex that directly activates lens-specific enhancers, such as the δ-crystallin enhancer, essential for early lens specification. This interaction is stage-dependent, with epistatic regulation between and Sox2 ensuring proper progression from ectodermal competence to placode formation. Additionally, SOX2 expression in the head is an early molecular triggered by signaling pathways like and FGF, marking the onset of lens induction. In retinal development, SOX2 is indispensable for maintaining retinal progenitor cells (RPCs), which give rise to all major retinal cell types. SOX2 sustains RPC multipotency and proliferation during embryogenesis, preventing premature differentiation and ensuring balanced . Loss-of-function mutations in SOX2 disrupt this maintenance, leading to severe ocular defects such as (complete absence of the eye) and (underdeveloped eye), which account for 10-20% of such cases in humans. These mutations impair RPC survival and identity, resulting in and other structural anomalies. SOX2 also contributes to inner ear development, particularly through its expression in the otic vesicle, where it drives neurosensory specification and prosensory domain formation. In the otic , SOX2 marks progenitor cells fated to become sensory hair cells and supporting cells, interacting with factors like Atoh1 to promote sensory throughout the otic vesicle. Conditional studies reveal that SOX2 is required for otic vesicle and the development of nonsensory regions in the , highlighting its role in coordinating morphological and cellular differentiation. Dysregulation of SOX2 expression, such as ectopic expansion or restriction via signaling, alters sensory patch boundaries and neurosensory fate. In adults, SOX2 supports the renewal of the by regulating stem and states in the limbal niche. SOX2 interacts with P63 to maintain limbal epithelial identity, enabling self-renewal and into stratified corneal layers. This pathway ensures epithelial and , with SOX2 expression persisting in basal limbal cells.

Role in Disease

Developmental Disorders

Mutations in the SOX2 gene are a leading cause of anophthalmia-microphthalmia (AIMS), also referred to as SOX2 , an autosomal dominant characterized by severe ocular malformations and multisystem involvement. Heterozygous pathogenic variants or deletions in SOX2 account for approximately 10-20% of cases of bilateral or severe , making it the most common single-gene for these defects. The has an estimated prevalence of about 1 in 250,000 live births. SOX2, a high-mobility group (HMG) box essential for early , requires precise dosage; disrupts neural competence and in the optic vesicle, leading to absent or underdeveloped eyes. Pathogenic variants in SOX2 are predominantly loss-of-function, including nonsense, frameshift, and missense mutations, as well as whole-gene or partial deletions encompassing the 3q26.33 locus. Mutations within the HMG box domain, which is critical for DNA binding and sequence-specific recognition, are particularly disruptive, often resulting in truncated proteins or impaired transcriptional activity. Approximately 60% of cases arise de novo, while the remainder are inherited, typically from unaffected mosaic parents or, less commonly, affected mothers due to variable expressivity. Common variants include frameshifts like p.Asn24ArgfsTer65, reported in about 20% of affected individuals. Associated clinical features extend beyond ocular anomalies to include esophageal atresia or tracheoesophageal fistula (in up to 40% of cases), brain malformations such as hippocampal hypoplasia or corpus callosum agenesis, intellectual disability or developmental delay (nearly universal), growth retardation, and genital anomalies like micropenis or cryptorchidism in males. Other manifestations may involve hypotonia, seizures, spasticity, and hypogonadotropic hypogonadism. Animal models have elucidated the mechanisms underlying SOX2-related disorders. Heterozygous Sox2 mice, particularly those with hypomorphic alleles or (e.g., Sox2β-geo/ΔENH), recapitulate key human phenotypes, including cerebral malformations, neural progenitor defects, hypoplasia, , and reduced retinal ganglion cells, demonstrating the dosage-sensitive role of Sox2 in and . These models show impaired and differentiation in neural tissues, mirroring the observed in patients. Diagnosis of SOX2 disorder relies on clinical evaluation combined with molecular . Criteria include bilateral or severe with or without systemic features; may reveal brain anomalies, and endoscopic assessment can identify esophageal defects. involves targeted of SOX2 (detecting ~76% of variants) followed by deletion/duplication analysis (identifying ~24%), often using methods like (MLPA) or array (aCGH). Confirmation of a heterozygous pathogenic variant or deletion establishes the , with available for at-risk pregnancies via or .

Cancer

SOX2 exhibits a dual role in cancer, acting as an in certain malignancies while functioning as a tumor suppressor in others, with its effects highly context-dependent across tumor types. In s, particularly those of the and , SOX2 amplification and overexpression are frequent events that drive tumorigenesis by promoting cancer stemness and . For instance, SOX2 amplification occurs in approximately 20-27% of non-small cell lung cancers (NSCLC), predominantly in the squamous subtype, where it enhances proliferation and anchorage-independent growth of tumor cells. In esophageal (ESCC), SOX2 overexpression reprograms squamous and sustains lineage survival, contributing to tumor initiation and metastatic potential. These oncogenic effects are linked to SOX2's ability to maintain a stem-like state in cancer cells, facilitating resistance to therapy and disease progression. Conversely, SOX2 demonstrates tumor-suppressive properties in gliomas, where its loss correlates with aggressive disease and poor patient outcomes. In high-grade gliomas, low SOX2 expression in primary tumors predicts unfavorable , as SOX2 normally restricts excessive and maintains cellular quiescence in stem cells (GSCs). In , SOX2 acts as an , with high expression promoting and through pathways such as epithelial-mesenchymal transition, and is associated with advanced stages and worse survival. This context-dependent function underscores SOX2's involvement in balancing maintenance against . As a key marker of cancer stem cells (CSCs), SOX2 regulates critical stemness factors such as and ALDH1, influencing tumor initiation and therapeutic resistance. Genome-wide CRISPR-Cas9 screens in GSCs have identified SOX2 as a direct regulator of (encoded by ), where SOX2 binds the PROM1 promoter to sustain CSC self-renewal and stress response capabilities. SOX2 also upregulates ALDH1A1 expression in CSCs, expanding the ALDH-high population responsible for spheroid formation and tumor propagation, as observed in head and neck squamous cell carcinomas. Clinically, elevated SOX2 serves as a in NSCLC, with high expression in 20-30% of cases indicating variable outcomes depending on subtype—favorable in squamous but adverse in —guiding risk stratification. Mechanistically, SOX2 enhances cancer cell through interactions with , forming complexes that drive progression and survival signaling. In various cancers, SOX2 cooperates with to amplify proliferative pathways, such as EGFR-mediated growth, while repressing antagonistic factors to sustain tumor expansion. Recent studies have further elucidated SOX2's role in , where its overexpression in 2025 cohorts promotes therapy-resistant and by reprogramming metabolic and stemness networks, positioning it as a driver of advanced disease.

Protein Interactions

Key Binding Partners

SOX2, a high-mobility-group (HMG) box , engages in direct physical interactions with several key protein partners to regulate across developmental contexts. One of its most prominent binding partners is OCT4 (also known as ), with which SOX2 forms a heterodimeric complex that binds to composite OCT-SOX motifs in enhancer regions, particularly those driving pluripotency gene expression in embryonic stem cells. This synergy is critical for cooperative DNA binding and transcriptional activation, as demonstrated by structural and functional studies showing that the OCT4-SOX2 interface enhances affinity for specific DNA sequences like the canonical composite motif. The interaction has been validated through co-immunoprecipitation (co-IP) assays and (ChIP) experiments, revealing co-occupancy at thousands of genomic sites enriched for pluripotency regulators. Within the core pluripotency network, SOX2 also directly interacts with NANOG and , facilitating their co-binding to shared target sites across the . These interactions enable the coordinated of self-renewal and differentiation genes, with ChIP-seq data indicating co-occupancy at thousands of genomic sites in embryonic cells, often overlapping with OCT4-bound regions to form an interconnected regulatory circuit. Yeast two-hybrid screens and co-IP confirm the protein-protein contacts, underscoring SOX2's role as a central hub in this network. In neural and sensory organ development, SOX2 binds PAX6, a paired-box essential for eye formation. The SOX2-PAX6 complex assembles on lens-specific enhancers, such as the δ-crystallin minimal enhancer, to initiate lens placode differentiation through cooperative DNA binding. This partnership has been established via yeast two-hybrid screening, co-IP, and electrophoretic mobility shift assays, highlighting how SOX2 modulates PAX6's transcriptional specificity during ocular . SOX2 further interacts with nucleophosmin 1 (NPM1), a nucleolar chaperone protein that promotes SOX2's nuclear retention and stability in pluripotent cells. Co-IP experiments in embryonic stem cells demonstrate that the SOX2-NPM1 complex persists during retinoic acid-induced differentiation, aiding in the maintenance of SOX2's localization and function. This binding, validated through immunoprecipitation-mass spectrometry, supports SOX2's nucleoplasmic activities beyond the nucleolus. Recent investigations have revealed non-transcriptional roles for SOX2 through cytosolic interactions, including direct to ribosomal proteins that modulate mRNA of metabolic pathways. In a 2024 study using BioID and co-IP in lines, cytosolic SOX2 was shown to associate with and 60S ribosomal subunits, influencing the of mRNAs involved in sugar metabolism, such as those in the and , as well as 93 mRNAs with expression patterns overlapping tissues of SOX2 significance, thereby linking SOX2 to cellular and fate decisions. Yeast two-hybrid assays corroborated these ribosomal contacts, expanding SOX2's functional repertoire beyond the .

Functional Complexes

SOX2 participates in several multi-protein complexes that orchestrate context-specific gene regulation, particularly in pluripotent and differentiating cells. These assemblies enable SOX2 to integrate with chromatin remodelers, co-activators, and repressive machinery, facilitating dynamic control over transcriptional programs essential for stem cell identity and lineage commitment. In embryonic stem cells (ESCs), SOX2 collaborates with OCT4 and NANOG to recruit the Mediator complex, which bridges enhancers and promoters to activate RNA polymerase II (Pol II) at pluripotency genes. This trimeric pioneer factor complex binds to nucleosomal DNA, opening chromatin and facilitating Mediator's interaction with Pol II's C-terminal domain, thereby promoting efficient transcription initiation and elongation at super-enhancers that maintain the ESC state. For instance, depletion of SOX2 disrupts these long-range chromatin interactions, leading to reduced Pol II occupancy and gene expression at target loci. SOX2 also engages in antagonistic interactions with the Polycomb repressive complex 2 (PRC2), competing to modulate neural during . By to regulatory regions of neural genes in neural precursors, SOX2 inhibits PRC2-mediated deposition of the repressive mark, thereby preventing premature closure and promoting timely activation of programs. This competitive dynamic ensures that SOX2 maintains an open epigenetic landscape, countering Polycomb's activity to balance pluripotency exit with neural lineage specification. The OCT4/SOX2/NANOG complex functions as a pioneer assembly that initiates chromatin accessibility at closed loci. These factors cooperatively distort nucleosomal DNA structures, recruiting ATP-dependent remodelers like BRG1 to evict histones and expose binding sites for downstream transcription factors, which is critical for establishing the pluripotency network in ESCs. Recent structural studies highlight how SOX2's HMG domain enhances DNA bendability within the complex, amplifying chromatin opening efficiency. Post-implantation, SOX2 and NANOG form a that represses posterior al genes to preserve epiblast pluripotency in the mouse embryo. This assembly maintains anterior-posterior patterning by suppressing genes like T and Mixl1 in the posterior epiblast, but NANOG subsequently repurposes to downregulate SOX2 itself, initiating pluripotency extinction and allowing posterior fate commitment; embryos lacking post-implantation NANOG retain ectopic posterior SOX2 expression, disrupting mesoderm formation. Additionally, SOX2 associates with co-activator complexes such as p300/CBP to drive acetylation and enhance transcription. p300/CBP acetylates like H3K27 at SOX2-bound enhancers, promoting an open state, while also acetylating SOX2 to modulate its and activity in ESCs; this cooperative mechanism amplifies super-enhancer activity and pluripotency gene expression.

Therapeutic and Research Applications

In

SOX2 serves as one of the core transcription factors, alongside OCT4, , and c-MYC (collectively known as OSKM), essential for cells into induced pluripotent cells (iPSCs). This process enables the generation of patient-specific pluripotent cells for regenerative applications, with SOX2 maintaining pluripotency by regulating genes involved in self-renewal and epigenetic remodeling. Optimizations for clinical-grade iPSCs have focused on integration-free delivery methods to minimize genomic risks, such as vectors or episomal plasmids, which achieve efficiencies of up to 0.1-1% while producing transgene-free cells suitable for therapeutic use. These advancements, including xeno-free media and chemical enhancements, have facilitated scalable production of iPSCs compliant with good manufacturing practices, as demonstrated in protocols yielding high-purity lines from human fibroblasts. In neural repair, SOX2 overexpression in neural stem cells (NSCs) enhances their therapeutic potential for conditions like (SCI) and posthemorrhagic . Following SCI in models, endogenous SOX2 expression upregulates in reactive , promoting reprogramming of NG2 glia into neuroblasts and supporting axonal regrowth, with SOX2 knockout impairing this process. Similarly, SOX2-modified NSCs transplanted into a model of posthemorrhagic significantly reduced ventricular enlargement compared to controls, increased doublecortin-positive neurons by over twofold, and improved motor and cognitive functions through effects and modulation of pathways. Preclinical studies from 2023 onward highlight SOX2's role in directing NSC differentiation toward neural lineages, though trials remain in early phases as of 2025. Ectopic SOX2 expression has shown promise in retinal regeneration, particularly by reprogramming into proliferative progenitors in mouse models of degeneration. In damaged retinas, SOX2 overexpression in increases their proliferation by up to fivefold and induces neuronal differentiation, restoring photoreceptor layers and improving in models like Pde6b rd10 degenerative mice. This approach counters age-related or injury-induced vision loss by reactivating developmental pathways, with SOX2 dosage precisely tuned to avoid aberrant proliferation; low levels promote amacrine and fates, while higher expression drives broader progenitor expansion. In N-methyl-N-nitrosourea-induced retinal degeneration models, SOX2-transduced generated functional neurons, partially reversing electroretinogram deficits. Despite these advances, challenges in SOX2-based regenerative therapies include the risk of formation from residual undifferentiated iPSCs or , which can occur in 10-20% of transplants in preclinical models unless mitigated by suicide systems or purification protocols. Precise dosage control of SOX2 is also critical, as overexpression restricts in high doses, leading to immature cell states, while underexpression impairs maintenance; studies in models show that SOX2 levels must be calibrated within a twofold range to ensure safe, directed lineage commitment. These trials build on SOX2's role in generating clinical-grade progenitors, focusing on subretinal to promote photoreceptor while for integration and functionality.

Targeting in Cancer

SOX2 has emerged as a promising therapeutic target in cancer due to its frequent overexpression in various malignancies, where it drives stemness, , and therapy resistance. Direct inhibition strategies focus on disrupting its DNA-binding activity via the HMG box domain. Preclinical studies have identified Dawson-type s, such as K6[P2W18O62], as nanomolar inhibitors of SOX2's DNA-binding capability, reducing activity and impairing tumor cell growth in models of lung and . Similarly, polyoxometalate derivatives like PW12 have shown efficacy in reversing resistance in cells by suppressing SOX2-mediated stemness and epithelial-mesenchymal transition. These small molecules remain in , with challenges in selectivity and limiting clinical translation. Gene-editing approaches, particularly -Cas9-based knockdown, have demonstrated potent antitumor effects in SOX2-dependent cancers. In 2025 functional screens, targeting of SOX2 reduced expression and dynamics in glioblastoma stem cells, highlighting its regulatory role in tumor initiation. Knockdown also significantly impaired spheroid and tumorsphere formation in stem cells, underscoring SOX2's maintenance of self-renewal in high-SOX2 tumors. In head and neck , targeted delivery via lipid nanoparticles eliminated 50% of tumors in preclinical mouse models by specifically ablating SOX2 in tumor cells. Indirect modulation of SOX2 expression offers alternative strategies to circumvent direct targeting difficulties. MicroRNA-145 (miR-145) mimics suppress SOX2 by binding its 3' , inhibiting proliferation and migration in and colorectal cancers. BET inhibitors, such as , downregulate SOX2 by disrupting recruitment to its enhancers, reducing stemness in NUT midline and models where SOX2-BRD4 complexes drive oncogenesis. The dual role of SOX2 complicates therapeutic targeting, as it functions as an in squamous cell carcinomas while exhibiting tumor-suppressive effects in other contexts, such as gastric cancer, necessitating context-specific agonists or antagonists to avoid unintended promotion of tumorigenesis. In the clinical pipeline, a phase II trial (NCT05242965) evaluates the STEMVAC multi-antigen vaccine, which includes SOX2 peptides to elicit immune responses against SOX2-expressing tumors, including non-small cell , in combination with standard therapies for advanced disease (initiated 2022, ongoing as of 2025). Preclinical data support SOX2 siRNA combined with to overcome in , but no dedicated early-phase siRNA trials have advanced to humans by late 2025.

References

  1. [1]
    SOX2 SRY-box transcription factor 2 [ (human)] - NCBI
    Sep 27, 2025 · This intronless gene encodes a member of the SRY-related HMG-box (SOX) family of transcription factors involved in the regulation of ...GeneNCBI OrthologsSOX2 SRY-box transcription ...
  2. [2]
    SOX2 gene: MedlinePlus Genetics
    Jul 2, 2025 · The SOX2 gene provides instructions for making a type of protein called a transcription factor. Transcription factors attach (bind) to specific regions of DNA.
  3. [3]
    Review SOX2 in development and cancer biology - ScienceDirect.com
    The transcription factor SOX2 is essential for embryonic development and plays a crucial role in maintaining the stemness of embryonic cells and various adult ...Review · 4. The Role Of Sox2 In... · 4.1. Sox2 In Developmental...
  4. [4]
    SOX2 protein biochemistry in stemness, reprogramming, and cancer
    Sep 2, 2019 · Here we provide a comprehensive review of the current knowledge on SOX2 protein modifications, their proposed relationship to the PI3K/AKT pathway, and ...Sox2 Secondary Modifications · Sox2 Protein Phosphorylation · Parpylation Of Sox2
  5. [5]
    Sox2 SRY (sex determining region Y)-box 2 [ (house mouse)] - NCBI
    Sep 15, 2025 · This intronless gene encodes a member of the SRY-related HMG-box (SOX) family of transcription factors involved in the regulation of embryonic development.
  6. [6]
    Entry - *184429 - SRY-BOX 2; SOX2 - OMIM - (OMIM.ORG)
    (2003) indicated that the single-exon SOX2 gene lies in an intron of the SOX2OT gene (616338), which is transcribed in the same orientation. ▻ Mapping. By ...<|control11|><|separator|>
  7. [7]
    A Sox2 distal enhancer cluster regulates embryonic stem cell ... - NIH
    Two gene-proximal enhancers, Sox2 regulatory region 1 (SRR1) and SRR2, display activity in reporter assays, but deleting SRR1 has no effect on pluripotency. We ...
  8. [8]
    Comparative genomics on SOX2 orthologs - PubMed
    SOX2 gene at human chromosome 3q26.33, SOX1 gene at 13q34, and SOX3 gene at Xq27.1 constitute a subfamily among the SOX gene family. Here, rat Sox2 and Xenopus ...
  9. [9]
    Functional Analysis of Chicken Sox2 Enhancers Highlights an Array ...
    Article. Functional Analysis of Chicken Sox2 Enhancers Highlights an Array of Diverse Regulatory Elements that Are Conserved in Mammals.
  10. [10]
    SOX2 - Transcription factor SOX-2 - Homo sapiens (Human) - UniProt
    SOX2 is a transcription factor that controls gene expression in embryonic development, keeps neural cells undifferentiated, and is critical for early ...
  11. [11]
    https://pmc.ncbi.nlm.nih.gov/articles/PMC12585912/
  12. [12]
    Structural basis for nuclear import selectivity of pioneer transcription ...
    Jan 4, 2021 · However, we found instead that, SOX2 residues Arg40, Lys42, and Arg43 were bound at the minor site (IMPα3 ARM domains 6–8; Fig. 2) and that SOX2 ...
  13. [13]
    Identification of the transactivation domain of the transcription factor ...
    Sox-2 contains a transactivation domain in its C-terminal half, containing a serine-rich region and the C terminus.
  14. [14]
    Cyclin-dependent Kinase-mediated Sox2 Phosphorylation ...
    In this study we have identified new phosphorylation sites on Sox2 and have further demonstrated that Cdk2-mediated Sox2 phosphorylation at Ser-39 and Ser-253 ...
  15. [15]
    Acetylation of Sox2 Induces its Nuclear Export in Embryonic Stem ...
    Jul 9, 2009 · With the exception of K123, all of the acetylated lysines reside within the HMG box of Sox2. To map the residues likely to be acetylated in vivo ...
  16. [16]
    Selective influence of Sox2 on POU transcription factor binding in ...
    Aug 11, 2015 · Sox2 binding selectively increases the affinity of Oct4 for the Sox/Oct motif. In contrast, Oct6 binds preferentially to MORE and is unaffected by Sox2.
  17. [17]
    An emerging molecular mechanism for the neural vs mesodermal ...
    Mar 29, 2011 · Unlike other Sox1B genes, Sox2 expression extends caudally from the neural tube to include the epiblast cells located adjacent to the primitive ...
  18. [18]
    A single cell characterisation of human embryogenesis identifies ...
    Jun 17, 2021 · We analysed a total of 29 embryos by single-cell RNA sequencing (scRNA-seq) using 10x Genomics Chromium (Supplementary Data 1). 13 out of 29 ...
  19. [19]
    https://www.nature.com/articles/cr201154
  20. [20]
    https://www.nature.com/articles/s41467-021-23758-w
  21. [21]
    Sox2+ adult stem/progenitor cells are important for tissue ... - NIH
    ... 1993) (Figure 1C). Moreover, we identified rare Sox2+ cells within the ... Lastly, we have identified Sox2+ stem cells in the lens epithelium that ...
  22. [22]
    https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(07)00172-5
  23. [23]
    Sox2 Up-regulation and Glial Cell Proliferation Following ...
    Nov 9, 2010 · These results demonstrate that up-regulation of Sox2 expression is associated with increased cell proliferation in the auditory nerve after injury.
  24. [24]
    Tissue expression of SOX2 - Summary - The Human Protein Atlas
    SOX2 is tissue enhanced in the brain and esophagus, mainly for neuronal signaling, and is detected in many tissues.
  25. [25]
    https://doi.org/10.1016/j.exer.2017.05.012
  26. [26]
    Regulation of Sox2 by STAT3 initiates commitment to the neural ...
    Further investigation revealed the existence of a novel signaling pathway during early neural development in which STAT3 directly regulates the Sox2 promoter ...
  27. [27]
    https://www.proteinatlas.org/ENSG00000181449-SOX2/tissue
  28. [28]
    https://www.cell.com/cell/fulltext/S0092-8674(05)00825-4
  29. [29]
    https://pubmed.ncbi.nlm.nih.gov/18447642/
  30. [30]
    A Sox2 distal enhancer cluster regulates embryonic stem cell ...
    Two gene-proximal enhancers, Sox2 regulatory region 1 (SRR1) and SRR2, are able to drive transgene expression in ES cells as well as multipotent neural ...
  31. [31]
    A Sox2 enhancer cluster regulates region-specific neural fates from ...
    We hypothesize that a downstream enhancer cluster, termed Sox2 regulatory regions 2–18 (SRR2–18), regulates Sox2 transcription in neural stem cells.
  32. [32]
    Mapping gene regulatory circuitry of Pax6 during neurogenesis
    Feb 9, 2016 · Pax6 is a highly conserved transcription factor among vertebrates and is important in various aspects of the central nervous system development.
  33. [33]
    Pax6 and SOX2 form a co-DNA-binding partner complex that ...
    We demonstrate that Pax6 initiates lens development by forming a molecular complex with SOX2 on the lens-specific enhancer elements, e.g., the δ-crystallin ...Missing: ChIP- | Show results with:ChIP-
  34. [34]
    https://pmc.ncbi.nlm.nih.gov/articles/PMC12005160/
  35. [35]
    https://www.nature.com/articles/celldisc201545
  36. [36]
    https://genesdev.cshlp.org/content/15/10/1272.short
  37. [37]
    https://doi.org/10.1016/j.cell.2009.02.038
  38. [38]
    Regulation of Stem Cell Pluripotency and Differentiation Involves a ...
    Expression of the Zfp42/Rex1 gene has long been used as a marker of undifferentiated stem cells and is regulated by Nanog, Sox2, and Oct4, and by the Wnt ...Introduction · Epigenetic Events Involving... · The Nanog/oct4/sox2...
  39. [39]
    A UTF1 -based selection system for stable homogeneously ...
    The 3′ enhancer element harbors a twin octamer sequence where the synergistic binding of Oct4 and Sox2 is essential for UTF1 expression in both mouse and human ...Cell Culture, Transfection... · Scid Mouse Teratoma Assay · Results
  40. [40]
    The Sox2-Oct4 Connection: Critical players in a much larger ... - NIH
    One of these studies focused on the genome-wide binding of Oct4, Sox2, Nanog, Klf4, c-Myc, Dax1, Rex1, Nac1 and Zpf281, as well as the genome-wide distribution ...
  41. [41]
    Stoichiometric and temporal requirements of Oct4, Sox2, Klf4, and c ...
    Aug 4, 2009 · Increasing relative Oct4 expression resulted in enhanced reprogramming efficiency, whereas increasing the relative ratio of either Sox2, Klf4, ...
  42. [42]
    Sox2 expression effects on direct reprogramming efficiency as ...
    Low Sox2 (LS) expression increased the efficiency of generating partially reprogrammed iPSCs in combination with OKM. Notably, we detected a significant ...Missing: Yamanaka | Show results with:Yamanaka
  43. [43]
    Sox2 expression effects on direct reprogramming efficiency as ...
    We conclude that Sox2 plays a crucial role in a dose-dependent manner in direct reprogramming of somatic cells to iPSCs.
  44. [44]
    C-MYC Transcriptionally Amplifies SOX2 Target Genes to Regulate ...
    Dec 11, 2014 · C-MYC and SOX2 target genes include cyclin-dependent kinases that regulate cell-cycle progression. iMOP cells continually divide but retain the ...
  45. [45]
    Sox2, a key factor in the regulation of pluripotency and neural ...
    In this review, we place particular emphasis on the biological functions of Sox2 in regulating pluripotency and early neural differentiation of ESCs and ...
  46. [46]
    Multipotent cell lineages in early mouse development depend on ...
    We have used gene targeting to inactivate Sox2, examining the phenotypic consequences in mutant embryos and in chimeras in which the epiblast is rescued with ...Missing: et | Show results with:et
  47. [47]
    Emerging cooperativity between Oct4 and Sox2 governs the ... - eLife
    Oct 11, 2024 · Although Oct4- or Sox2-KO embryos develop apparently normal EPI, they fail to give rise to embryonic stem cells (ESCs) (Avilion et al., 2003; ...
  48. [48]
    Sox2 transcription network acts as a molecular switch to regulate ...
    In this review, I focus on the transcription regulatory network centered around Sox2 to shed light on the molecular regulatory mechanism underlying the biology ...Sox2 Transcription Network... · Neural Stem Cells And Sox2 · Sox2 Target Genes And Stem...
  49. [49]
    In Vivo Analysis of Ascl1 Defined Progenitors Reveals Distinct ...
    Nov 21, 2007 · Our results reveal that Ascl1 is a common molecular marker of early progenitors of both neurons and oligodendrocytes in the adult brain.
  50. [50]
    A cell fate decision map reveals abundant direct neurogenesis ...
    Mar 28, 2024 · We show that basal radial glial cells undergo abundant symmetric amplifying divisions, and frequent self-consuming direct neurogenic divisions, bypassing ...
  51. [51]
    A human-specific enhancer fine-tunes radial glia potency and corticogenesis
    **Summary of SOX2 and Human-Specific Enhancers in Neocortex Expansion/Radial Glia:**
  52. [52]
    Sox2 Up-regulation and Glial Cell Proliferation Following ...
    These results demonstrate that up-regulation of Sox2 expression is associated with increased cell proliferation in the auditory nerve after injury.
  53. [53]
    The Role of SOX2 and SOX9 Transcription Factors in the ... - MDPI
    Our results confirmed previously published data showing the up-regulation of SOX2 and SOX9 in reactive astrocytes after injury [33,36,37,49,50,51]. Also in ...The Role Of Sox2 And Sox9... · 2. Materials And Methods · 3. Results
  54. [54]
    Sox2-overexpressing neural stem cells alleviate ventricular ...
    The results showed that NSC Sox2 attenuated the ventricular enlargement caused by posthemorrhagic hydrocephalus and improved neurological function.
  55. [55]
    Sox2 deficiency causes neurodegeneration and impaired ...
    Aug 1, 2004 · Sox2 deficiency causes neurodegeneration and impaired neurogenesis in the adult mouse brain Available ... microcephaly and motor abnormalities.
  56. [56]
    Pax6 and SOX2 form a co-DNA-binding partner complex ... - PubMed
    May 15, 2001 · We demonstrate that Pax6 initiates lens development by forming a molecular complex with SOX2 on the lens-specific enhancer elements, e.g., the ...
  57. [57]
    Stage-dependent modes of Pax6-Sox2 epistasis regulate lens ...
    The transcription factors Pax6 and Sox2 have been implicated in early events in lens induction and have been proposed to cooperate functionally.
  58. [58]
    Involvement of Sox1, 2 and 3 in the early and subsequent molecular ...
    An essential molecular event in lens induction is the 'turning on' of the transcriptional regulators SOX2/3 in the Pax6-expressing ectoderm.
  59. [59]
    Fgf receptor signaling plays a role in lens induction - PubMed - NIH
    This analysis establishes a role for Fgfr signaling in lens induction and defines a genetic pathway in which Fgfr and Bmp7 signaling converge on Pax6 expression ...
  60. [60]
    The master transcription factor SOX2, mutated in anophthalmia ...
    Mar 13, 2020 · Mutations in the key transcription factor, SOX2, alone account for 20% of anophthalmia (no eye) and microphthalmia (small eye) birth defects ...
  61. [61]
    Novel SOX2 mutations and genotype-phenotype correlation in ...
    Mutations in SOX2 are known to result in a spectrum of severe ocular phenotypes in humans, also typically associated with other systemic defects. Ocular ...
  62. [62]
    A novel heterozygous SOX2 mutation causing anophthalmia ...
    Heterozygous mutations in the SOX2 gene are the most common monogenic form of anophthalmia/microphthalmia, as they are reported in up to 10-15% cases. Here, we ...
  63. [63]
    SOX2 is required for inner ear growth and cochlear nonsensory ...
    Jun 21, 2019 · Our study demonstrates a novel role for SOX2 in early otic morphological development, and provides insights into the temporal and spatial ...
  64. [64]
    The prosensory function of Sox2 in the chicken inner ear relies on ...
    Jan 23, 2012 · The results show that hair cells derive from Sox2-positive otic progenitors and that Sox2 directly activates Atoh1 through a transcriptional ...
  65. [65]
    Jagged 1 regulates the restriction of Sox2 expression in ... - PubMed
    Jagged 1 regulates the restriction of Sox2 expression in the developing chicken inner ear: a mechanism for sensory organ specification. Development. 2011 Feb ...<|separator|>
  66. [66]
    SOX2 Regulates P63 and Stem/Progenitor Cell State in the Corneal ...
    We propose that SOX2/P63 pathway is an essential regulator of corneal stem/progenitor cells while mutations in SOX2 or P63 may disrupt epithelial regeneration.
  67. [67]
    SOX2 anophthalmia syndrome - PubMed
    May 15, 2005 · Heterozygous, de novo, loss-of-function mutations in SOX2 have been shown to cause bilateral anophthalmia.
  68. [68]
    Mutations in SOX2 cause anophthalmia-esophageal-genital (AEG ...
    We report heterozygous, loss-of-function SOX2 mutations in three unrelated individuals with Anophthalmia-Esophageal-Genital (AEG) syndrome.
  69. [69]
    SOX2 Disorder - PubMed
    Jul 30, 2020 · The phenotypic spectrum of SOX2 disorder includes anophthalmia and/or microphthalmia, brain malformations, developmental delay / intellectual disability, ...
  70. [70]
    Review of 37 patients with SOX2 pathogenic variants collected by ...
    Sep 25, 2021 · SOX2 variants and deletions are a common cause of anophthalmia and microphthalmia (A/M). This article presents data from a cohort of patients ...
  71. [71]
    SOX2 Disorder - GeneReviews® - NCBI Bookshelf - NIH
    Feb 23, 2006 · The phenotypic spectrum of SOX2 disorder includes anophthalmia and/or microphthalmia, brain malformations, developmental delay / intellectual disability, ...Diagnosis · Clinical Characteristics · Management · Genetic Counseling
  72. [72]
    SOX2 anophthalmia syndrome: 12 new cases demonstrating ...
    Heterozygous mutations in SOX2, a SOX1B‐HMG box transcription factor, have been found in up to 10% of individuals with severe microphthalmia or anophthalmia ...
  73. [73]
    SOX2 is a dose-dependent regulator of retinal neural progenitor competence
    ### Summary of Mouse Model for Sox2 in Eye Development
  74. [74]
    SOX2 Is an Amplified Lineage Survival Oncogene in Lung and ... - NIH
    Oct 4, 2009 · SOX2 expression is required for proliferation and anchorage-independent growth of lung and esophageal cell lines, as shown by RNA interference ...Missing: review | Show results with:review
  75. [75]
    SOX2 drives esophageal squamous carcinoma by reprogramming ...
    Sep 2, 2025 · SOX2 is a potent oncodriver for various squamous cancers, but the underlying mechanism is largely unknown. Here we uncover a role of SOX2 in ...
  76. [76]
    Glioma SOX2 expression decreased after adjuvant therapy
    Nov 12, 2019 · Lower SOX2 expression was seen in those patients who received adjuvant therapy. Low expression of SOX2 in primary HGG predicts poor prognosis.
  77. [77]
    SOX2 function in cancers: Association with growth, invasion ...
    SOX2 has capacity of increasing growth and metastasis of cancer cells. It functions as double-edged sword and has ability of suppressing tumor progression.
  78. [78]
    CRISPR screen reveals SOX2 as a critical regulator of CD133 and ...
    Oct 16, 2025 · The surface protein CD133 marks glioblastoma stem cells (GSCs), cells capable of overcoming therapeutic pressures and correlate with more ...Missing: ALDH1 | Show results with:ALDH1
  79. [79]
    Regulation of Head and Neck Squamous Cancer Stem Cells ... - NIH
    Sep 15, 2016 · SOX2 in turn increased the ALDH+ cell population by direct upregulation of ALDH1A1 and enhanced spheroid and tumor formation. This is the first ...
  80. [80]
    SOX2 gene amplification and protein overexpression are associated ...
    SOX2 amplification and upregulation are frequent events in squamous cell carcinomas of the lung and are associated with indicators of favorable prognosis.
  81. [81]
    The molecular pathogenesis of SOX2 in prostate cancer
    Feb 20, 2025 · SOX2 is crucial for the initiation, progression, invasion, metastasis, and treatment resistance of prostate cancer.
  82. [82]
    Dissecting the role of distinct OCT4-SOX2 heterodimer ... - Nature
    Aug 28, 2015 · Our results show that the OCT4-SOX2 configuration formed on the canonical composite plays the most critical role in pluripotency.
  83. [83]
    An extended transcriptional network for pluripotency of embryonic ...
    More interestingly, 9 of 35 are occupied by at least 4 of 6 factors (Nanog, Sox2, Dax1, Nac1, Oct4, and Klf4, p-value < 5.3 × 10−8). In Figure 6B, target ...
  84. [84]
    Core transcription factors, Oct4, Sox2 and Nanog, individually form ...
    We found that all three core transcription factors, namely Oct4, Sox2 and Nanog, individually formed complexes with nucleophosmin (Npm1).Missing: retention | Show results with:retention
  85. [85]
    Core transcription factors, Oct4, Sox2 and Nanog, individually form ...
    Nov 12, 2010 · Npm1/Sox2 interaction changes during differentiation. Both Sox2 and Npm1 protein levels are changing when ES cells start to differentiate. To ...Missing: retention | Show results with:retention
  86. [86]
    https://www.cell.com/cell-reports/fulltext/S2211-1247(24)01158-6
  87. [87]
    Multifaceted SOX2-chromatin interaction underpins pluripotency ...
    Dec 15, 2023 · Sox2 deficiency in mice leads to epiblast formation failure and embryonic lethality shortly after implantation (11). Because of the limited ...
  88. [88]
    SOX2 primes the epigenetic landscape in neural precursors ...
    We show that SOX2 deficiency in cultured adult hipNPCs reduces activation of “poised” bivalently marked (H3K4me3 and H3K27me3) transcription factors, including ...
  89. [89]
    The pioneer factor OCT4 requires the chromatin remodeller BRG1 to ...
    Mar 13, 2017 · Here, we discover that the pluripotency-associated pioneer factor OCT4 binds chromatin to shape accessibility, transcription factor co-binding, ...
  90. [90]
    NANOG is repurposed after implantation to repress Sox2 and begin ...
    Aug 18, 2025 · Here, we show that SOX2 is required for post-implantation pluripotent identity in the mouse, and cells that lose SOX2 expression in the ...
  91. [91]
    Molecular basis for SOX2-dependent regulation of super-enhancer ...
    Nov 1, 2023 · Pioneer transcription factors (TFs) like SOX2 are vital for stemness and cancer through enhancing gene expression within transcriptional ...Results · Binding Of Sox2 To Sox... · Sox2- And Sox2 Binding...
  92. [92]
    Induced pluripotent stem cells (iPSCs): molecular mechanisms of ...
    Apr 26, 2024 · We consider the molecular mechanisms and dynamics of somatic cell reprogramming as well as the numerous methods available to induce pluripotency ...
  93. [93]
    Optimization of episomal reprogramming for generation of human ...
    Our study provides a detailed stepwise protocol for improved generation of integration-free iPSCs from human fibroblasts by transfection with episomal vectors.
  94. [94]
    Generation of clinical-grade human induced pluripotent stem cells in ...
    Nov 12, 2015 · Clinical-grade hiPSCs were derived by integration-free Sendai virus-based reprogramming kit in Xeno-free pluriton™ reprogramming medium or X ...Missing: optimizations | Show results with:optimizations
  95. [95]
    vivo reprogramming of NG2 glia enables adult neurogenesis and ...
    Mar 5, 2021 · SOX2 is required cell-autonomously for SCI-induced reprogramming of NG2 glia. To understand how SCI induces cell reprogramming, we focused on ...
  96. [96]
    Human induced neural stem cells support functional recovery in ...
    Jun 1, 2023 · Our iNSCs could be an alternative and optimal cell type for future clinical application to regenerate the spinal cord in patients with spinal ...
  97. [97]
    Sox2 regulates Müller glia reprogramming and proliferation in the ...
    Morpholino-mediated knockdown of Sox2 expression resulted in decreased numbers of proliferating Müller glia, while induced overexpression of Sox2 stimulated ...
  98. [98]
    Sox2 Plays a Role in the Induction of Amacrine and Müller Glial ...
    We used a gain-of-function analysis and found that Sox2 promotes amacrine cell differentiation in a retinal explant culture prepared from an E17 mouse embryo.
  99. [99]
    Sox2 regulates Müller glia reprogramming and proliferation in the ...
    This study is the first to identify a functional role for Sox2 during Müller glial-based regeneration of the vertebrate retina.
  100. [100]
    Improving the safety of human pluripotent stem cell therapies using ...
    Jun 1, 2020 · In preclinical models, hPSC-derived cell populations have been reported to form teratomas, other types of tumor, or cysts with varying ...
  101. [101]
    SOX2 is a dose-dependent regulator of retinal neural progenitor ...
    Collectively, these results show that precise regulation of SOX2 dosage is critical for temporal and spatial regulation of retinal progenitor cell ...
  102. [102]
    jCyte Announces Publication of Phase I/IIa Safety Study of Retinal ...
    Aug 25, 2025 · jCyte Announces Publication of Phase I/IIa Safety Study of Retinal Progenitor Cells in Retinitis Pigmentosa in Frontiers in Cellular ...Missing: SOX2 | Show results with:SOX2
  103. [103]
    Stem/progenitor cell-based transplantation for retinal degeneration
    Sep 23, 2020 · We provide a comprehensive overview on the progression of clinical trials for RD treatment using four types of stem/progenitor cell-based transplantation.
  104. [104]
    Identification of a Polyoxometalate Inhibitor of the DNA Binding ...
    (22, 23) Together, these studies suggest that Sox2 acts at the onset of carcinogenesis as well as in cancer stem cells with a high proliferative potential that ...
  105. [105]
    Polyoxometalate inhibition of SOX2-mediated tamoxifen resistance ...
    Sep 2, 2024 · Here, we examine the potential inhibitory effect of different polyoxometalate (POM) derivatives on SOX2 transcription factor in tamoxifen-resistant breast ...
  106. [106]
    CRISPR screen reveals SOX2 as a critical regulator of CD133 and ...
    Oct 16, 2025 · In this study, we employed a CRISPR-Cas9 functional screen to deconvolute CD133 dynamics in tumors. This led us to establish that SOX2 is a key ...Missing: knockdown tumorsphere
  107. [107]
    A comprehensive overview of ovarian cancer stem cells: correlation ...
    May 7, 2025 · Knockdown of SOX2 significantly impairs spheroid formation efficiency, reinforcing its essential role in CSC maintenance. Additionally, SOX2 is ...
  108. [108]
    CRISPR Therapy Eliminates 50% of Head and Neck Tumors
    Mar 11, 2025 · Tel Aviv University researchers used CRISPR to cut the SOX2 gene from head and neck cancer cells, eliminating 50% of tumors in mice.Missing: knockdown formation
  109. [109]
    miR-145-5p Suppresses Breast Cancer Progression by Inhibiting ...
    miR-145-5p played a suppressive role in the proliferation of breast cancer cells by targeting SOX2, and miR-145-5p is a putative biomarker for risk assessment.
  110. [110]
    Activation of SOX2 expression by BRD4-NUT oncogenic fusion ...
    This study established that BRD4-NUT stimulates SOX2 expression to support proliferation and to inhibit differentiation.
  111. [111]
    Targeting non-canonical activation of GLI1 by the SOX2-BRD4 ...
    May 6, 2021 · Targeting non-canonical activation of GLI1 by the SOX2-BRD4 transcriptional complex improves the efficacy of HEDGEHOG pathway inhibition in melanoma.
  112. [112]
    The dark side of SOX2: cancer - a comprehensive overview - PMC
    SOX2 has been implicated in growth, tumorigenicity, drug resistance, and metastasis in at least 25 different cancers.Regulation Of Sox2... · Micrornas And Sox2... · Table 3. Micrornas...
  113. [113]
    A Multiple Antigen Vaccine (STEMVAC) for the Treatment of Patients ...
    This phase II trial tests whether CD105/Yb-1/SOX2/CDH3/MDM2-polyepitope plasmid DNA vaccine (STEMVAC) works to shrink tumors in patients with stage IV ...
  114. [114]
    SOX2 knockdown with siRNA reverses cisplatin resistance in ... - NIH
    siSOX2 overcomes cisplatin resistance by regulating APE1 signaling, providing a new target for overcoming cisplatin resistance in NSCLC.Missing: trials | Show results with:trials