Affinage

POU5F1

POU domain, class 5, transcription factor 1 · UniProt Q01860

Round 2 corrected
Length
360 aa
Mass
38.6 kDa
Annotated
2026-04-28
130 papers in source corpus 44 papers cited in narrative 44 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

POU5F1 (OCT4) is a POU-domain transcription factor that functions as a quantitative master regulator of pluripotency, where precise expression levels dictate whether embryonic stem cells self-renew, differentiate into trophectoderm, or adopt primitive endoderm/mesoderm fates (PMID:10742100, PMID:9814708). It heterodimerizes with SOX2 on composite sox-oct cis-regulatory elements to drive autoregulatory and feedforward transcriptional circuits—including activation of NANOG, FGF4, and LIN28B—and cooperates with KLF4 to activate additional ES-specific targets (PMID:16153702, PMID:15860457, PMID:19816951). Structurally, OCT4 employs a unique surface-exposed α-helical linker between its POU sub-domains as a protein–protein interaction hub that recruits competing co-regulators (Klf5, Cbx1, Set1a, β-catenin, Dax1), and uses both POUS and POUHD domains to engage and cooperatively unwrap nucleosomal DNA as a pioneer transcription factor (PMID:23376973, PMID:35171666, PMID:32327602, PMID:37327775). Its activity is modulated by ERK2-mediated phosphorylation at T234/S235 (which disrupts DNA binding), SirT1-dependent deacetylation (which gates the naive-to-primed transition), and sumoylation (required for G1/S progression), integrating signaling inputs to control cell-cycle progression and lineage commitment (PMID:22474382, PMID:27732856, PMID:23495099).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1990 High

    Molecular cloning of Oct-4 established POU5F1 as a new POU-family transcription factor with a distinctive bipartite DNA-binding domain, providing the molecular entry point for all subsequent functional studies.

    Evidence cDNA cloning with in vitro transcription/translation, DNA-binding assays, and deletion analysis

    PMID:1690859

    Open questions at the time
    • No in vivo function established
    • Transcriptional targets unknown
    • Protein structure beyond POU domain uncharacterized
  2. 1994 High

    Protein expression mapping across early development revealed that OCT4 is restricted to pluripotent lineages (ICM, ES cells) after blastocyst cavitation, and its proximal promoter is negatively regulated by nuclear hormone receptors, establishing the first evidence for lineage-restricted expression and transcriptional control of POU5F1 itself.

    Evidence Immunohistochemistry/confocal microscopy in murine embryos and cultured cells; promoter dissection with binding and reporter assays in EC cells

    PMID:7958450 PMID:8152920

    Open questions at the time
    • No functional consequence of mis-expression tested
    • Post-transcriptional regulation mechanisms unresolved
  3. 1998 High

    Gene knockout demonstrated that OCT4 is essential for pluripotent cell identity in the mammalian embryo—without it, ICM cells adopt trophoblast fate—and revealed a paracrine role in FGF-4-mediated trophectoderm maintenance, answering the central question of whether OCT4 is required for pluripotency.

    Evidence Oct4-null mouse embryos, embryo analysis, FGF-4 rescue

    PMID:9814708

    Open questions at the time
    • Downstream transcriptional targets unidentified
    • Whether OCT4 level matters (vs. presence/absence) untested
  4. 2000 High

    Conditional expression studies established that OCT4 acts as a quantitative rheostat: small increases drive endoderm/mesoderm differentiation while repression triggers trophectoderm, resolving how a single factor controls three distinct fates.

    Evidence Conditional expression/repression in ZHBTc4 ES cells with defined phenotypic readouts

    PMID:10742100

    Open questions at the time
    • Molecular mechanism of dose-dependent target selection unknown
    • Direct genomic targets not yet mapped
  5. 2005 High

    Genome-scale ChIP and targeted studies revealed that OCT4 and SOX2 co-occupy hundreds of target promoters in ES cells and form autoregulatory/feedforward loops with NANOG—including direct binding to the Nanog and Pou5f1 enhancers—defining the core pluripotency transcriptional circuitry.

    Evidence Genome-scale ChIP location analysis in human ES cells; EMSA, ChIP, mutagenesis, RNAi in mouse/human ES cells

    PMID:15860457 PMID:15988017 PMID:16153702

    Open questions at the time
    • Structural basis of OCT4-SOX2 heterodimerization on DNA unresolved
    • Roles of individual target genes in maintaining pluripotency not dissected
  6. 2005 High

    Discovery of the OCT4-CDX2 reciprocal repression axis and identification of co-regulators (EWS, HMG-1) showed that OCT4 actively suppresses alternative lineage programs and employs co-activators to modulate its transactivation strength.

    Evidence Co-immunoprecipitation with forced expression in ES cells (CDX2); bacterial two-hybrid, GST pull-down, co-IP (EWS); phage display plus co-IP (HMG-1)

    PMID:11099378 PMID:15917470 PMID:16325584

    Open questions at the time
    • Structural details of OCT4-CDX2 interface unknown
    • Genome-wide targets of repression by OCT4 not mapped
  7. 2007 High

    Epistasis experiments showed SOX2's essential function is to maintain OCT4 expression levels (OCT4 overexpression rescues Sox2-null ES cells), and OCT4's activity is negatively regulated by PIASy-mediated nuclear relocalization, revealing new layers of upstream and spatial control.

    Evidence Inducible Sox2-null ES cells with Oct3/4 rescue; yeast two-hybrid, co-IP, fluorescence microscopy for PIASy

    PMID:17515932 PMID:17991485

    Open questions at the time
    • Whether PIASy regulation is physiologically relevant in embryos untested
    • How OCT4 level is sensed at the protein level remains unclear
  8. 2009 High

    Single-factor reprogramming experiments demonstrated that OCT4 alone is sufficient to reprogram neural stem cells to pluripotency in both mouse and human, establishing OCT4 as the indispensable core of the reprogramming machinery and identifying co-regulators Dax1 and Klf4 as modulators of its DNA-binding and cooperative activity.

    Evidence Single-factor lentiviral reprogramming with teratoma/chimera validation; co-IP, EMSA, ChIP for Dax1 and Klf4 interactions

    PMID:19203577 PMID:19528230 PMID:19718018 PMID:19816951

    Open questions at the time
    • Mechanism by which OCT4 accesses closed chromatin during reprogramming unknown
    • Kinetics of OCT4 target engagement during reprogramming uncharacterized
  9. 2012 High

    Mass spectrometry-based phosphosite mapping identified 14 OCT4 phosphorylation sites and showed that ERK2-mediated phosphorylation at T234/S235 in the homeodomain disrupts DNA binding and impairs reprogramming, providing the first direct link between signaling kinases and OCT4 transcriptional competence.

    Evidence LC-MS/MS phosphosite mapping, phosphomimetic mutagenesis, in vitro kinase assays, reprogramming assays

    PMID:22474382

    Open questions at the time
    • In vivo stoichiometry of phosphorylation under different signaling states unknown
    • Phosphatases responsible for dephosphorylation unidentified
  10. 2013 High

    Crystal structure of the OCT4 POU domain revealed a structured α-helical linker (absent in OCT1) that serves as a protein–protein interaction interface for recruiting epigenetic regulators; linker mutations abolish reprogramming, solving a long-standing question about how OCT4 differs structurally from other POU factors.

    Evidence X-ray crystallography, point mutagenesis, reprogramming assays, mass spectrometry interactome

    PMID:23376973

    Open questions at the time
    • Full-length OCT4 structure not available
    • Dynamic conformational changes during target engagement uncharacterized
  11. 2016 High

    Studies of OCT4's acetylation state and chromatin integrator function showed that SirT1-mediated deacetylation gates the naive-to-primed pluripotency transition via Otx2 enhancer binding, and genome-wide analyses demonstrated OCT4 binds low-accessibility regions to recruit signal-dependent factors (RAR:RXR, β-catenin), establishing OCT4 as a signal integrator at closed chromatin.

    Evidence Deacetylation assays and acetylation mutants with ChIP in transitioning ESCs; ChIP-seq/ATAC-seq with gain/loss-of-function models

    PMID:27499297 PMID:27732856

    Open questions at the time
    • Full set of acetylation-dependent binding site switches not mapped
    • How OCT4 initially accesses compacted chromatin mechanistically unresolved
  12. 2017 High

    CRISPR knockout of POU5F1 in human (and subsequently bovine) embryos revealed species-specific roles: human OCT4 is required for both trophectoderm gene expression and epiblast gene maintenance, unlike mouse where it primarily suppresses trophectoderm in ICM.

    Evidence CRISPR-Cas9 editing in human zygotes with single-cell transcriptomics; CRISPR-Cas9/SCNT in bovine embryos

    PMID:28953884 PMID:29483258

    Open questions at the time
    • Mechanistic basis for species-specific differences in OCT4 function not elucidated
    • Downstream effectors mediating OCT4's trophectoderm role in human unknown
  13. 2020 High

    Cryo-EM structures of OCT4-SOX2 on nucleosomes at base-pair resolution showed how OCT4 uses alternative domain configurations (POUS or POUHD) depending on motif position to differentially distort nucleosomal DNA, providing the structural basis for pioneer factor activity.

    Evidence Cryo-EM single-particle analysis with chemical mapping, crosslinking MS, mutagenesis, and biochemical binding assays

    PMID:32327602 PMID:32678275

    Open questions at the time
    • How OCT4 navigates heterogeneous chromatin contexts in vivo not captured
    • Competition with linker histone H1 not characterized in cellular settings
  14. 2022 High

    The OCT4 linker interface was shown to mediate competitive binding between Klf5 and Cbx1/Ctr9/Cdc73, with balanced occupancy required for pluripotency maintenance; separately, endothelial-specific OCT4 knockout revealed a non-stem-cell role in vascular homeostasis via direct ABCG2 transactivation.

    Evidence Linker point mutations in ESCs with co-IP, transcriptomics, and rescue; EC-specific conditional KO with scRNA-seq and ChIP

    PMID:35171666 PMID:35325071

    Open questions at the time
    • Whether linker-mediated competitive binding occurs in other cell types unknown
    • Full scope of OCT4 functions in adult somatic cells uncharacterized
  15. 2023 High

    High-resolution cryo-EM of OCT4 on LIN28B nucleosomes demonstrated that multiple OCT4 molecules bind cooperatively, with POUHD acting as a wedge to unwrap ~25 bp of DNA, enabling opening of H1-condensed chromatin arrays—providing a complete structural mechanism for pioneer factor-mediated chromatin remodeling.

    Evidence Cryo-EM at multiple configurations, biochemical unwrapping assays, genomic data integration

    PMID:37327775

    Open questions at the time
    • Whether cooperative multi-OCT4 binding occurs at all genomic targets or only at specific loci is unclear
    • In vivo dynamics of nucleosome unwrapping by OCT4 not measured

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: (1) the structural basis of full-length OCT4 with post-translational modifications bound to nucleosomal targets; (2) the mechanistic basis for species-specific differences in OCT4 function during embryogenesis; (3) the full repertoire and physiological significance of OCT4 functions in adult somatic cells beyond stem cells.
  • No full-length OCT4 structure with PTMs resolved
  • Species-specific downstream effector networks not mapped
  • Adult somatic OCT4 roles are documented in only one tissue context

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 9 GO:0140110 transcription regulator activity 9
Localization
GO:0000228 nuclear chromosome 4 GO:0005634 nucleus 3
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-162582 Signal Transduction 3 R-HSA-4839726 Chromatin organization 3
Partners
CDX2CTNNB1DAX1KLF4KLF5NANOGSETD1ASOX2
Complex memberships
OCT4-NANOG network complexOCT4-SOX2 heterodimerOCT4-SOX2-KLF4 complex

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 Oct-4 (POU5F1) was cloned and characterized as a novel POU-family transcription factor; deletion analysis demonstrated that DNA-binding activity is mediated by a POU domain encoded in an open reading frame corresponding to a 324-amino-acid protein, establishing it as a new member of the POU family with a distinct POU domain type. cDNA cloning, in vitro transcription/translation, DNA-binding assays, protease-clipping analysis, deletion analysis Nature High 1690859
1994 Oct-4 protein is expressed in embryonic stem cells, oocyte pronuclei, and all cleavage-stage blastomeres, but is restricted to the inner cell mass after trophectoderm differentiation at the blastocyst stage; it is also expressed in primitive endoderm cells, where protein levels exceed RNA levels, indicating post-transcriptional regulation. Immunohistochemistry using confocal microscopy in cultured cells and murine embryos Developmental biology High 7958450
1994 The Oct-4 proximal promoter contains an overlapping set of regulatory elements including a high-affinity Sp1-binding site and three direct repeats of an AGGTCA-like sequence; members of the steroid-thyroid hormone receptor superfamily (including ARP-1 and RAR) negatively regulate Oct-4 expression through these elements. Binding assays and transient transfection assays in EC cells Nucleic acids research Medium 8152920
1997 The C-terminal transactivation domain of Oct-4 is subject to cell-type-specific regulation mediated by the Oct-4 POU domain; the POU domain suppresses C-domain activity in a cell-type-specific manner, and this correlates with differences in Oct-4 phosphorylation status. Gal4-fusion transactivation assays in differentiated and undifferentiated cell lines, phosphopeptide analysis Molecular and cellular biology Medium 8972195
1998 Oct4 is essential for the identity of the pluripotent founder cell population in the mammalian embryo; Oct4-deficient embryos reach the blastocyst stage but inner cell mass cells are not pluripotent and instead differentiate along the trophoblast lineage; Oct4 also determines paracrine FGF-4 signaling from stem cells to the trophectoderm to maintain trophoblast proliferation. Gene knockout (Oct4-null mouse embryos), embryo analysis, rescue with FGF-4 Cell High 9814708
2000 The precise level of Oct-3/4 governs three distinct ES cell fates: a less than twofold increase in expression causes differentiation into primitive endoderm and mesoderm, while repression of Oct-3/4 induces dedifferentiation to trophectoderm; a critical amount is required to sustain stem-cell self-renewal, establishing Oct-3/4 as a master regulator of pluripotency acting as a quantitative rheostat. Conditional expression and repression system (ZHBTc4 ES cells), gene expression analysis Nature genetics High 10742100
2000 Oct-4 interacts with HMG-1 (and HMG-2) proteins identified by phage display screening; HMG-1 enhances Oct-4 distance-dependent transactivation in P19 EC cells when co-expressed, establishing HMG-1 as a co-activator of Oct-4. Phage display screening of P19 EC cell cDNA library, co-immunoprecipitation in mammalian cells, co-expression transactivation assays Journal of molecular biology Medium 11099378
2001 Suppression-subtractive hybridization identified putative downstream genes of Oct-4, including Rex-1, Sox-2, creatine kinase B, Makorin 1, importin beta, histone H2A.Z, and ribosomal protein S7 as Oct-4-regulated targets in embryonic stem cells. Suppression-subtractive hybridization, colony hybridization, Northern blot analysis Biochemical and biophysical research communications Low 11401518
2005 OCT4 and SOX2 co-occupy a substantial portion of their target genes genome-wide in human ES cells, including genes encoding developmentally important transcription factors, and together with NANOG form autoregulatory and feedforward regulatory loops constituting the core transcriptional regulatory circuitry of ES cells. Genome-scale chromatin immunoprecipitation (ChIP) location analysis in human ES cells Cell High 16153702
2005 Oct-4 and Sox2 bind cooperatively to a composite sox-oct cis-regulatory element within the Nanog proximal promoter; mutagenesis of this element abolishes pluripotent-specific transcription; EMSA and ChIP confirmed direct heterodimer binding in living mouse and human ES cells; RNAi knockdown of Oct4 or Sox2 reduces Nanog expression. Mutagenesis, EMSA, chromatin immunoprecipitation, RNAi knockdown, reporter assays The Journal of biological chemistry High 15860457
2005 The Oct4/Sox2 complex binds a composite sox-oct element within the Pou5f1 distal enhancer to create a positive autoregulatory loop; ChIP confirmed binding in living mouse and human ESCs; RNAi knockdown of either Oct4 or Sox2 reduced both genes' enhancer activities and endogenous expression levels. Chromatin immunoprecipitation (ChIP), RNAi, in vitro binding with ESC nuclear extracts, reporter assays Molecular and cellular biology High 15988017
2005 Oct3/4 and Cdx2 form a protein complex that mediates reciprocal repression of their target genes in ES cells; Cdx2 overexpression is sufficient to generate trophoblast stem cells by overcoming Oct3/4 activity; Oct3/4 repression alone can induce TE differentiation without requiring Cdx2. Co-immunoprecipitation, forced expression/repression in ES cells, cell fate analysis Cell High 16325584
2005 Ewing's sarcoma protein (EWS) interacts directly with the POU domain of Oct-4 via three independent sites on EWS; this interaction was confirmed by GST pull-down, co-immunoprecipitation, and co-localization; ectopic expression of EWS enhances Oct-4 transactivation activity. Bacterial two-hybrid screening, GST pull-down, co-immunoprecipitation, co-localization, transactivation assays Stem cells (Dayton, Ohio) Medium 15917470
2006 Klf4 cooperates with Oct3/4 and Sox2 to activate Lefty1 expression in ES cells by binding to the proximal element of the Lefty1 promoter as a mediating factor; this three-factor cooperativity was required for ES-specific enhancer activity, revealing a novel mode of Oct3/4 action. Functional screening of ES-specific transcription factors, luciferase reporter assays, DNA microarray analysis, co-expression experiments Molecular and cellular biology Medium 16954384
2006 A protein interaction network centered on Nanog (and Oct4) was defined in mouse ES cells; affinity purification of Nanog followed by mass spectrometry identified Oct4 and multiple co-repressor pathway components as interacting partners; the network is enriched for nuclear factors critical for ES cell state maintenance. Affinity purification under native conditions, mass spectrometry, co-immunoprecipitation validation Nature High 17093407
2007 Sox2 is dispensable for activation of Oct-Sox enhancers in ES cells; instead, the essential function of Sox2 is to regulate transcription factors that control Oct3/4 expression levels; forced expression of Oct3/4 rescues pluripotency of Sox2-null ES cells, placing Sox2 upstream of Oct3/4 expression maintenance. Inducible Sox2-null mouse ES cells (conditional knockout), rescue by Oct3/4 overexpression, gene expression analysis Nature cell biology High 17515932
2007 Tpt1 (a cancer-associated factor in Xenopus oocytes) activates Oct4 and Nanog transcription upon nuclear transfer; depletion of Tpt1 transcripts reduces Oct4/Nanog transcription in transplanted HeLa nuclei, while elevation of Tpt1 causes earlier activation; RAR-gamma represses Oct4 transcription in oocytes. Xenopus oocyte nuclear transfer, mass spectrometry identification of oocyte proteins, siRNA depletion, mRNA injection Current biology Medium 17442571
2007 PIASy interacts with Oct4 via the Oct4 POU domain and the SAP-domain-containing N-terminus of PIASy in vivo; PIASy inhibits Oct4-mediated transcriptional activation and sequesters Oct4 from the vicinity of Cajal bodies and splicing speckles to the nuclear periphery, independent of sumoylation activity; PIAS1 and PIAS3 also interact with Oct4. Yeast two-hybrid screen, co-immunoprecipitation, fluorescence microscopy/nuclear localization, transactivation reporter assays Journal of molecular biology Medium 17991485
2008 High-throughput MEGAshift binding assay revealed that POU5F1 forms novel distinct classes of DNA complexes at conserved genomic loci, including novel functional combinations of POU5F1 half-sites; binding strength correlates with active transcription in ES cells. MEGAshift (microarray evaluation of genomic aptamers by shift), ChIP, recombinant protein binding assays Genome research Medium 18212089
2008 Oct3/4 is required for primordial germ cell (PGC) specification; chimeric embryos with Oct3/4-null ES cells failed to form PGCs; rescue with an additional Oct3/4 transgene restored PGC specification, establishing Oct3/4 as essential for the germ cell fate determination. Chimeric embryo analysis with ZHBTc4 ES cells, conditional transgene rescue, doxycycline-inducible system Developmental biology High 18395706
2009 OCT4 alone is sufficient to reprogram adult mouse neural stem cells (which endogenously express Sox2, Klf4, and c-Myc) to pluripotency, establishing OCT4 as the minimal reprogramming factor needed when complementary factors are already present. Single-factor lentiviral transduction, iPS cell generation, teratoma formation, chimera and germline transmission Cell High 19203577
2009 OCT4 is sufficient to reprogram human fetal neural stem cells to pluripotency with a single factor, demonstrating conservation of OCT4's core reprogramming function in human cells. Single-factor lentiviral OCT4 expression, iPS cell characterization (gene expression, epigenetics, in vitro/in vivo pluripotency) Nature High 19718018
2009 Dax1 (an orphan nuclear hormone receptor) interacts with Oct3/4 via the POU-specific domain of Oct3/4; this interaction abolishes Oct3/4 DNA binding activity as shown by pull-down and gel-shift assays; Dax1 inhibits Oct3/4 binding to the Nanog and Oct3/4 promoter/enhancer regions in ChIP assays, and overexpression of Dax1 induces ES cell differentiation. Co-immunoprecipitation, GST pull-down, EMSA, chromatin immunoprecipitation, reporter assays, overexpression Molecular and cellular biology High 19528230
2009 Paf1/PD2 interacts with Oct3/4 and RNA polymerase II in mouse ES cells; knockdown of Paf1/PD2 reduces Oct3/4, SOX2, Nanog, and Shh levels and alters ES cell self-renewal, establishing Paf1/PD2 as a component of the Oct3/4 regulatory network. Co-immunoprecipitation, knockdown (siRNA/KO), gene expression analysis, cell cycle analysis Stem cells (Dayton, Ohio) Medium 19821493
2009 Klf4 interacts directly with Oct4 and Sox2 proteins when expressed at reprogramming levels; the Klf4 C-terminal zinc-finger domain mediates the interaction; Oct4/Sox2/Klf4 co-occupy the Nanog promoter; dominant-negative Klf4 disrupting the complex strongly inhibits reprogramming. Co-immunoprecipitation, dominant-negative mutant analysis, chromatin immunoprecipitation, reporter assays Stem cells (Dayton, Ohio) High 19816951
2010 Oct-4 controls ES cell-cycle progression; Oct-4 down-regulation blocks G0/G1 progression; Oct-4 directly represses the p21 gene (Cdkn1a), and p21 protein is induced upon Oct-4 downregulation in ZHBTc4 ES cells; functional domain analysis showed overall integrity of Oct-4 domains is required for S-phase entry stimulation. Inducible Oct-4 repression (ZHBTc4), cell cycle analysis, deletion analysis of Oct-4 domains, p21 expression analysis The Biochemical journal Medium 19968627
2011 Stabilized β-catenin forms a protein complex with Oct-4 and enhances Oct-4 transcriptional activity in a TCF-independent manner; this β-catenin effect on pluripotency is not dependent on TCF-mediated Wnt signaling, as shown by dominant-negative TCF strategies and β-catenin C-terminal truncation mutants. GSK-3 double knockout ES cells, co-immunoprecipitation, dominant-negative TCF, β-catenin truncation mutants, reporter assays Cell stem cell High 21295277
2012 LC-MS/MS identified 14 phosphorylation sites on human OCT4; functional analysis showed phosphorylation at T234 and S235 within the homeobox region negatively regulates OCT4 by interrupting sequence-specific DNA binding; phosphomimetic mutations reduce transcriptional activation and reprogramming efficiency; ERK2 phosphorylates these sites in vitro. Liquid chromatography-mass spectrometry, phosphomimetic mutagenesis, reporter assays, reprogramming efficiency assays, in vitro kinase assays Proceedings of the National Academy of Sciences of the United States of America High 22474382
2013 The structure of the Oct4 POU domain bound to DNA revealed that the linker between the two DNA-binding sub-domains is structured as a surface-exposed α-helix (unlike the unstructured linker of Oct1); point mutations in this α-helix alter or abolish reprogramming activity without affecting other Oct4 functions; mass spectrometry of the interactome showed the linker recruits key epigenetic players to Oct4 target genes. X-ray crystallography, point mutagenesis, reprogramming assays, mass spectrometry interactome Nature cell biology High 23376973
2013 Zebrafish Pou5f1 occupies SOX-POU binding sites before the onset of zygotic transcription and activates the earliest zygotic genes, positioning Pou5f1 and SOX-POU sites at the center of the vertebrate zygotic gene activation (ZGA) network. ChIP-seq, transcriptomics, in situ hybridization, zebrafish MZspg mutant analysis Science (New York, N.Y.) High 23950494
2013 Oct4 post-translational modifications (phosphorylation and sumoylation) form feedback loops regulating Akt signaling and interaction with Hmgb2 and the SET complex; phosphorylated Oct4 promotes Akt activation and Hmgb2 interaction to preserve H3K27me3 in daughter cells; non-phosphorylated Oct4 inactivates Akt and initiates DNA damage response; Oct4 sumoylation is required for G1/S progression. Co-immunoprecipitation, phosphorylation/sumoylation mutants, Akt activity assays, chromatin analysis in mouse ES cells Stem cells (Dayton, Ohio) Medium 23495099
2015 The OCT4-SOX2 heterodimer configuration on a canonical Hoxb1-like composite element (juxtaposed binding sites) plays a more critical role in inducing and maintaining pluripotency than other OCT4-SOX2 configurations; SOX2 mutants that selectively disrupt this configuration impair iPSC generation and ESC self-renewal rescue. SOX2 interface mutants, iPSC reprogramming assays, ESC rescue assays Scientific reports Medium 26314899
2015 An Oct4 pseudogene-derived lncRNA (Oct4P4) forms a complex with the SUV39H1 histone methyltransferase to direct H3K9me3 and HP1α to the ancestral Oct4 promoter, silencing Oct4 during mESC differentiation; targeting Oct4P4 in fibroblasts re-activates Oct4 self-renewal features. RNA immunoprecipitation, co-immunoprecipitation, ChIP, siRNA/overexpression in mESCs and MEFs Nature communications Medium 26158551
2016 Set1a specifically interacts with Oct4 (but not Sox2, Klf4, or Myc) in a Wdr5-independent manner; Set1a is recruited to Oct4 target gene promoters and required for H3K4 methylation and transcriptional activation at these sites; Set1a knockout impairs ESC maintenance, iPSC generation, and generation of Oct4-positive ICM in vivo. Co-immunoprecipitation, ChIP-seq, gene expression profiling, gene knockout (mouse embryos and ESCs) Stem cells (Dayton, Ohio) High 26785054
2016 OCT4 binds low-accessible genomic regions and functions as an integrator of pluripotency and signal-induced differentiation by recruiting co-regulators and signal-dependent transcription factors (RAR:RXR or β-catenin) to enhancers; OCT4 overexpression in kidney cells enables signal-dependent activation of otherwise unresponsive genes. Genomic ChIP-seq, ATAC-seq, gain- and loss-of-function genetic models, ectopic expression in somatic cells Molecular cell High 27499297
2016 SirT1 deacetylates Oct4; reduced SirT1 activity during the naive-to-primed pluripotency transition leads to hyper-acetylated Oct4 that binds an Otx2 enhancer to induce Otx2 expression, which in turn reorganizes Oct4 to activate the primed pluripotency gene network. Deacetylation assays, acetylation mutants, ChIP, gene expression analysis in ESCs undergoing naive-to-primed transition Cell reports Medium 27732856
2017 CRISPR-Cas9 knockout of POU5F1 in human embryos compromised blastocyst development; transcriptomics showed downregulation of both trophectoderm genes (CDX2) and pluripotent epiblast regulators (NANOG) in POU5F1-null cells, indicating a broader role for OCT4 in human embryogenesis compared to mouse. CRISPR-Cas9 genome editing in human zygotes, single-cell transcriptomics Nature High 28953884
2018 OCT4 knockout in bovine embryos (via CRISPR-Cas9 + SCNT) showed that OCT4 is required for NANOG expression in the ICM but not for suppression of CDX2 in the ICM, mimicking findings in human (but not mouse) embryos; this established species-specific roles for OCT4 in the second lineage segregation. CRISPR-Cas9 knockout, somatic cell nuclear transfer, immunofluorescence, blastocyst analysis Proceedings of the National Academy of Sciences of the United States of America High 29483258
2020 Cryo-EM structures of OCT4-SOX2 bound to nucleosomes at two preferred positions revealed that OCT4 uses one of its two DNA-binding domains (POUS or POUHD) to engage nucleosomal DNA; depending on motif location, OCT4-SOX2 differentially distorts nucleosomal DNA—at one position removing DNA from histones H2A and H3, at an inverted motif inducing only local distortions. Cryo-electron microscopy, in vitro binding at base-pair resolution, mutagenesis Science (New York, N.Y.) High 32327602
2020 OCT4 preferentially binds its target DNA sequence near the nucleosome entry/exit site; crosslinking mass spectrometry showed OCT4 contacts the histone H3 N-terminal region near the entry/exit site; linker histone H1 competes with OCT4 for nucleosome binding. Cryo-EM single-particle analysis, chemical mapping, crosslinking mass spectrometry, mutational analysis, biochemical binding assays Scientific reports High 32678275
2022 The OCT4 POU linker interface mediates competing yet balanced interactions: in ESCs, OCT4 interacts with Klf5 (decreased in linker mutants), and separately with Cbx1, Ctr9, and Cdc73 (increased in linker mutants); restoring expression of Klf5, Cbx1, or Cdc73 individually rescues pluripotency of linker mutant ESCs, demonstrating competitive binding at the linker interface. Oct4 linker point mutations in ESCs, co-immunoprecipitation, transcriptomics, rescue by individual factor manipulation Science advances High 35171666
2022 EC-specific OCT4 knockout in mice caused increased lipid and LGALS3+ cell accumulation, increased endothelial activation, endothelial-to-mesenchymal transitions, plaque neovascularization, and mitochondrial dysfunction; ABCG2 was identified as a direct OCT4 transcriptional target in endothelial cells, and the OCT4/ABCG2 axis maintains EC metabolic homeostasis by regulating intracellular heme and ROS. EC-specific conditional KO, single-cell RNA sequencing, EC lineage tracing, ChIP for ABCG2, functional metabolic assays Cardiovascular research High 35325071
2022 OCT4 interprets nucleosome flexibility by using both DNA-binding domains (POUS for specific sequence recognition and POUHD for nonspecific DNA contact); binding propagates and stabilizes open nucleosome conformations; the magnitude of effect depends on binding site position and histone tail mobility. Molecular dynamics simulations, experimental biochemical binding assays, mutational analysis Nucleic acids research Medium 36130732
2023 High-resolution cryo-EM structures of nucleosomes containing human LIN28B DNA complexed with OCT4 DNA-binding region revealed three OCT4 molecules bound simultaneously: two use POUS domains and one uses POUS-loop-POUHD; POUHD acts as a wedge to unwrap ~25 bp of nucleosomal DNA; multiple OCT4s cooperatively open H1-condensed nucleosome arrays containing the LIN28B nucleosome. Cryo-EM structural determination, biochemical unwrapping assays, genomic data analysis, ESRRB-nucleosome-OCT4 co-structure determination Molecular cell High 37327775

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Induced pluripotent stem cell lines derived from human somatic cells. Science (New York, N.Y.) 7290 18029452
2005 Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 3476 16153702
2000 Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nature genetics 2796 10742100
1998 Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 2598 9814708
2007 Reprogramming of human somatic cells to pluripotency with defined factors. Nature 2190 18157115
2007 In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 1966 17554336
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2010 Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 1451 20881960
2009 A census of human transcription factors: function, expression and evolution. Nature reviews. Genetics 1191 19274049
2008 Induced pluripotent stem cells generated without viral integration. Science (New York, N.Y.) 1161 18818365
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2008 MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature 1105 18806776
2009 MicroRNA-145 regulates OCT4, SOX2, and KLF4 and represses pluripotency in human embryonic stem cells. Cell 938 19409607
2017 Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science (New York, N.Y.) 934 28473536
2005 Interaction between Oct3/4 and Cdx2 determines trophectoderm differentiation. Cell 929 16325584
2007 Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells. Nature cell biology 902 17515932
2006 A protein interaction network for pluripotency of embryonic stem cells. Nature 888 17093407
2005 Transcriptional regulation of nanog by OCT4 and SOX2. The Journal of biological chemistry 861 15860457
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