Affinage

ETV2

ETS translocation variant 2 · UniProt O00321

Length
342 aa
Mass
36.6 kDa
Annotated
2026-06-09
100 papers in source corpus 48 papers cited in narrative 48 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ETV2/ER71 is a pioneer ETS transcription factor that acts as a master regulator of hematoendothelial lineage specification, governing the progression of FLK1+ mesoderm into vascular and hematopoietic fates while suppressing alternative cardiac fate (PMID:18462699, PMID:21911838, PMID:21989919). As a pioneer factor it binds nucleosomal DNA at otherwise closed chromatin, displaces nucleosomes at clustered ETS sites, and recruits the BRG1 chromatin remodeler to open and maintain endothelial gene enhancers with increased H3K27ac (PMID:35550615, PMID:35864091). It primes hematoendothelial enhancers ahead of transcriptional activation, and the transition from binding to enhancer activation drives fate commitment (PMID:37330911). ETV2 partners with chromatin- and DNA-modifying enzymes—the H3K9 demethylase KDM4A to relieve repressive H3K9me3 at target genes, and TET1/TET2 to demethylate promoters such as Robo4 for endothelial-specific expression—and it recruits the repressor REST to silence non-endothelial lineage genes (PMID:39811655, PMID:29618782, PMID:40495012). ETV2 establishes an ETS hierarchy by directly activating downstream regulators including Scl/Tal1, Fli1, GATA2, Erg, and Sox7, with the program subsequently maintained by Fli1 through ETS switching after ETV2 expression ceases (PMID:25802403, PMID:21911838, PMID:24727028, PMID:24762086). It cooperates with co-factors GATA2, OVOL2, FoxC2/Sox17, and VEZF1 on target enhancers to drive endothelial and hematopoietic gene activation (PMID:24583263, PMID:25267199, PMID:25179465, PMID:36923254). ETV2 is activated downstream of BMP/Notch/Wnt, VEGF-FLK1, PKA/CREB, and calcineurin–NFATc3 signaling, and it dose-dependently partitions endothelial versus hematopoietic/hemogenic fate (PMID:18462699, PMID:28279709, PMID:22267325, PMID:28419336, PMID:35333649, PMID:35649376). Its expression is transient, terminated post-transcriptionally by let-7 microRNAs, and its reactivation in endothelium after injury drives vascular regeneration via upregulation of FLK1/VEGFR2 (PMID:24036310, PMID:26586661).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2002 Medium

    Established the basic molecular architecture of ER71 as a nuclear ETS transcriptional activator before its developmental role was known.

    Evidence Deletion mutagenesis and reporter assays mapping localization, DNA-binding, and transactivation domains on the MMP-1 promoter

    PMID:12087183

    Open questions at the time
    • No developmental or lineage function identified
    • MMP-1 target not connected to vascular biology
  2. 2006 Medium

    Identified the first ER71 protein partner, showing its activity is subject to negative regulation by an interacting protein.

    Evidence Reciprocal in vitro and in vivo binding with TSGA/Jmjd1a plus reporter repression

    PMID:16619273

    Open questions at the time
    • Functional relevance to lineage specification not tested
    • Single lab
  3. 2008 High

    Defined ETV2 as a master mesodermal regulator downstream of BMP/Notch/Wnt and conserved across vertebrates, answering where it sits in lineage specification.

    Evidence ESC differentiation with pathway inhibition/rescue, mouse knockout, and zebrafish ortholog overexpression/mosaic analysis

    PMID:18270322 PMID:18462699

    Open questions at the time
    • Direct chromatin targets not yet identified
    • Mechanism of transcriptional activation undefined
  4. 2011 High

    Resolved the precise developmental window and downstream effectors, showing ETV2 drives FLK1+ mesoderm into vascular/hematopoietic fate while repressing cardiac fate.

    Evidence Null embryo analysis, genetic fate mapping, and rescue identifying Scl, Fli1, GATA2 as effectors; zebrafish lineage tracing of endocardial nfatc1 induction

    PMID:21911838 PMID:21989916 PMID:21989919

    Open questions at the time
    • Whether targets are bound directly versus indirectly not fully resolved
    • Chromatin-level mechanism unknown
  5. 2012 High

    Placed ETV2 within upstream signaling and feedback circuits, establishing how VEGF-FLK1, PKA/CREB, and Wnt converge on its expression and activity.

    Evidence Promoter/CRE binding analysis with dominant-negative CREB, beta-catenin rescue of ER71-suppressed cardiogenesis, GFP reporter null analysis of hemogenic endothelium

    PMID:22267325 PMID:22343916 PMID:22570122 PMID:22733530

    Open questions at the time
    • Genome-wide binding landscape not yet defined
    • Hierarchy among downstream targets only partially ordered
  6. 2014 High

    Assembled the ETV2 cofactor network and the ETS-switching maintenance mechanism, explaining how a transient factor establishes a self-sustaining program.

    Evidence Co-IP/GST pulldown with GATA2 and OVOL2, ChIP of Fli1/Sox7 promoters, FOX:ETS composite enhancer cooperativity with FoxC2/Sox17

    PMID:24583263 PMID:24727028 PMID:24762086 PMID:25179465 PMID:25267199

    Open questions at the time
    • How cofactor combinations are selected at specific enhancers unknown
    • Stoichiometry of complexes undefined
  7. 2015 High

    Defined the genome-wide ETV2 enhancer program and its role in injury-induced regeneration, and identified microRNA effectors and upstream epigenetic regulators.

    Evidence ChIP-seq establishing ETS hierarchy, conditional knockout/ischemia models with FLK1 rescue and epistasis, miR-130a CRISPR knockout, LSD1 epistasis in zebrafish

    PMID:25722433 PMID:25802403 PMID:26512114 PMID:26565905 PMID:26586661

    Open questions at the time
    • Pioneer activity not yet directly demonstrated
    • Chromatin remodeler partners not yet identified
  8. 2017 High

    Extended ETV2 function to cell migration, lymphatic and proliferation programs, and identified additional upstream signals (Ca2+-NFATc3, VEGF, Foxh1) controlling threshold expression.

    Evidence ChIP-seq/ATAC-seq of Rhoj and Yes1, IP3R-NFATc3 knockout/rescue, VEGF inhibition/rescue in zebrafish, genome-wide CRISPR screen

    PMID:28279709 PMID:28419336 PMID:28912455 PMID:29232705 PMID:33115267

    Open questions at the time
    • Mechanism by which ETV2 dose is converted to distinct fates unresolved
    • Direct versus indirect nature of some targets unclear
  9. 2018 Medium

    Demonstrated ETV2 partners with DNA-modifying enzymes and can reprogram non-endothelial cells, revealing an epigenetic basis for endothelial-specific gene activation.

    Evidence Co-IP with TET1/TET2 and Robo4 promoter demethylation, ChIP-seq/RNA-seq of GBM/neural stem cell transdifferentiation, ChIP-seq of Vegfr3/Lyve1 lymphatic targets

    PMID:29527330 PMID:29618782 PMID:29753018

    Open questions at the time
    • Direct demonstration of nucleosome engagement still lacking
    • Generality of TET recruitment across targets untested
  10. 2022 High

    Directly established ETV2 as a pioneer factor that engages nucleosomal DNA and recruits chromatin remodelers, the central mechanistic insight unifying its lineage-instructive activity.

    Evidence Nucleosome binding assays, ATAC-seq/ChIP-seq with BRG1 recruitment in ESC models, ZRS limb enhancer nucleosome displacement, dosage and feedforward network analysis

    PMID:35333649 PMID:35531980 PMID:35550615 PMID:35649376 PMID:35864091

    Open questions at the time
    • Determinants of pioneer site selection genome-wide unresolved
    • How BRG1 recruitment is targeted not fully defined
  11. 2023 Medium

    Showed ETV2 primes enhancers prior to activation and identified VEZF1 as a direct cofactor, separating chromatin binding from transcriptional output.

    Evidence scRNA-seq/ATAC-seq of fate intermediates, yeast two-hybrid/Co-IP/GST pulldown with VEZF1 and Flt1 reporter/knockout

    PMID:36923254 PMID:37330911

    Open questions at the time
    • Trigger converting primed enhancers to active state unknown
    • Single lab for VEZF1 interaction
  12. 2024 Medium

    Defined how ETV2 simultaneously activates target genes via KDM4A demethylation and is itself controlled by transcriptional regulators, with disease relevance in pulmonary hypertension.

    Evidence Co-IP and H3K9me3 ChIP with KDM4A double conditional knockouts, BCL6B repression in hiPSCs, PPARgamma promoter activation with Etv2 haploinsufficient pulmonary hypertension model

    PMID:39075623 PMID:39391221 PMID:39811655

    Open questions at the time
    • Whether KDM4A is broadly required at all ETV2 targets unknown
    • Causal mechanism linking Etv2 haploinsufficiency to pulmonary hypertension incomplete
  13. 2025 High

    Established that ETV2 pioneer activity both activates endothelial genes and actively represses alternative fates by recruiting REST, with GABPA as a downstream cofactor.

    Evidence CUT&RUN, scRNA-seq, scATAC-seq, and functional screening with candidate validation

    PMID:40495012

    Open questions at the time
    • Mechanism of REST recruitment by ETV2 undefined
    • Genome-wide repressive target set not exhaustively mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ETV2 dose, cofactor availability, and chromatin state are integrated to deterministically partition individual cells between endothelial, hemogenic, and hematopoietic fates remains unresolved.
  • No single-cell mechanistic model linking ETV2 dose to fate choice
  • Rules governing pioneer site selection unknown
  • Order and dependency of remodeler/demethylase/repressor recruitment undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 4 GO:0140097 catalytic activity, acting on DNA 2
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-4839726 Chromatin organization 4 R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
BRG1GATA2KDM4AOVOL2RESTTET1TET2VEZF1

Evidence

Reading pass · 48 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 ER71 is a constitutively nuclear protein whose intracellular localization depends on a portion of the ETS domain (amino acids 276-315). The N-terminus of ER71 negatively regulates DNA binding, while the C-terminus dramatically enhances DNA binding activity. ER71 possesses a potent N-terminal transactivation domain (amino acids 1-157) and directly activates the matrix metalloproteinase-1 promoter via an E74 site. Deletion mutagenesis, reporter assays, nuclear localization analysis Nucleic acids research Medium 12087183
2006 TSGA/Jmjd1a interacts with ER71 both in vitro and in vivo; the N-terminus of TSGA and C-terminus of ER71 mediate complex formation. TSGA represses ER71-dependent transcriptional activation of the MMP-1 promoter. Co-immunoprecipitation, in vitro binding assay, reporter assay Journal of cellular biochemistry Medium 16619273
2008 ER71 acts downstream of BMP, Notch, and Wnt signaling to regulate FLK1+ mesoderm specification. Inhibition of BMP, Notch, and Wnt signaling decreased FLK1+ mesoderm and ER71 expression; enforced ER71 expression rescued FLK1+ mesoderm generation blocked by these inhibitors. Er71-deficient mice lacked FLK1 expression and displayed severe blood and vessel defects reminiscent of Flk1 null mice. Embryonic stem cell differentiation, pathway inhibition, genetic knockout, gain-of-function rescue Cell stem cell High 18462699
2008 Human ETV2/ER71 and mouse ER71 are functional orthologs of zebrafish Etsrp. Overexpression of mouse ER71 caused expansion of hemangioblast and vascular endothelial lineages in zebrafish. Etsrp functions cell-autonomously in inducing myeloid lineage, and the choice of endothelial versus myeloid fate depends on combinatorial effects of etsrp, scl, and alk8. Zebrafish overexpression, mosaic analysis, morpholino knockdown Blood High 18270322
2011 Etv2 is dispensable for generating primitive Flk-1+/PDGFRα+ mesoderm but required for the progression of these cells into Flk-1+/PDGFRα- vascular/hematopoietic mesoderm. Key downstream targets include Scl, Fli1, and GATA2. Expression of Scl or Fli1 alone could restore HPCs/ECs in Etv2-null background. VEGF potently and rapidly induces Etv2 in Flk-1+ mesoderm. ESC differentiation, Etv2-null embryo analysis, re-expression rescue experiments, gene expression profiling Blood High 21911838
2011 In the absence of ER71, cells that would normally become hematopoietic and endothelial lineages are redirected to cardiac lineages, including cardiomyocytes. ER71-expressing cells give rise to hematopoietic and endothelial lineages in wild-type, but contribute to cardiac lineage in Er71 mutants. ER71 overexpression repressed cardiogenesis. Er71-EYFP transgenic mouse, Er71-Cre genetic fate mapping, FACS, transcriptional profiling, inducible ES/EB system Development (Cambridge, England) High 21989919
2011 Etsrp-expressing vascular endothelial/endocardial progenitors differentiate as cardiomyocytes in the absence of Etsrp function. Etsrp directly induces endocardial nfatc1 expression to regulate endocardial differentiation. Etsrp inhibits myocardial differentiation through a distinct mechanism from endocardial induction. Foxc1a interaction with Etsrp is required to initiate endocardial development but dispensable for inhibition of myocardial differentiation. Zebrafish morpholino knockdown, mutant analysis, lineage tracing Development (Cambridge, England) High 21989916
2011 Foxc1a and Foxc1b directly regulate etsrp expression in angioblasts. ChIP showed Foxc1a/b binding to an enhancer 2.3 kb upstream of etsrp containing a consensus FOX binding site. Combined knockdown of foxc1a/b decreased etsrp expression at early developmental stages. EMSA, ChIP, morpholino knockdown, transgenic reporter analysis Circulation research High 22135404
2012 ER71 specifies Flk-1+PDGFRα- hemangiogenic mesoderm by negatively regulating cardiac and Wnt signaling pathway genes. ER71 inhibits Wnt signaling through VE-cadherin-independent and VE-cadherin-dependent (VE-cadherin/β-catenin/Flk-1 complex formation) mechanisms. Enforced β-catenin rescued cardiogenic mesoderm in the context of ER71 overexpression. ESC differentiation, gain/loss-of-function, β-catenin rescue experiments, gene expression analysis Blood High 22343916
2012 PKA/CREB signaling activates Etv2 transcription to trigger endothelial and hematopoietic cell differentiation. Two CRE sequences in the Etv2 promoter and 5'-UTR were identified; CREB directly binds these CRE sites. Dominant negative CREB completely inhibited PKA-elicited Etv2 expression and EC/HPC induction from ESCs. Promoter analysis, CREB binding confirmation, dominant-negative CREB, PKA inhibition, ex vivo embryo culture Stem cells (Dayton, Ohio) High 22267325
2012 SRY binds to and activates the Er71 promoter. In turn, ER71 binds to the Sox9 promoter and activates Sox9 transcription; mutation of the ER71 binding site suppressed this activation. SOX9 also binds the Er71 promoter, and Sox9 downregulation reduced Er71 levels, forming a positive autoregulatory loop between ER71 and SOX9 in testis. Promoter binding assays, site-directed mutagenesis, dominant-negative ER71, ChIP, luciferase reporter assays The Journal of biological chemistry High 22613723
2012 ETV2 is required for the formation of hemogenic endothelium; ETV2 deficiency results in a complete absence of hemogenic endothelium in differentiating ES cells and gastrulating embryos. ETV2::GFP transgenic mouse, ES cell differentiation, FACS sorting, in vivo embryo analysis Developmental dynamics High 22733530
2012 ETV2 acts prior to or at the time of FLK1 expression in mesodermal precursors. ETV2 re-expression in Etv2-/- Flk1-negative precursors drives hematopoiesis specification and switches on SCL, GATA2, and FLI1 expression. SCL re-expression in Etv2-/- cells fully rescues hematopoiesis, while FLI1 or GATA2 re-expression provides only limited rescue. Cre-mediated ETV2 deletion, Flk1-Cre, ESC differentiation rescue experiments Stem cells (Dayton, Ohio) High 22570122
2013 Etv2 expression alone is sufficient to transdifferentiate fast skeletal muscle cells into functional blood vessels in vivo. The canonical Wnt pathway is important for induction of transdifferentiation, while the VEGF pathway provides a maturation signal for endothelial fate. Mammalian myoblasts, but not other cell types examined, induced vascular gene expression upon Etv2 overexpression. Heat shock-inducible Etv2 zebrafish transgene, time-lapse imaging, lineage tracing, immunostaining, pharmacological/transgenic/morpholino approaches PLoS biology High 23853546
2013 Forced expression of Etv2 rescued both hematopoietic and endothelial potential of differentiating Flk1-/- and Etv2-/- cells, whereas forced Flk1 expression rescued only Flk1-/- but not Etv2-/- cells. This demonstrates that Etv2 functions downstream of or parallel to Flk1 and that disruption of Etv2 expression is responsible for early phenotypes of Flk1 mutant embryos. Inducible viral rescue of knockout ESCs, EB differentiation Genesis Medium 23606617
2013 Post-transcriptional repression by let-7 family microRNAs contributes to Etv2 downregulation during vascular development. The etv2 3'UTR contains binding sites for let-7 miRNAs; ectopic let-7a repressed the etv2 3'UTR and blocked endogenous Etv2 protein expression. Etv2 protein persisted in maternal-zygotic dicer1 mutant zebrafish embryos. Inducible Etv2 knockdown, 3'UTR reporter assays, miRNA overexpression, dicer1 mutant analysis Developmental biology Medium 24036310
2014 Etv2 interacts with Gata2 in vitro and in vivo; the interaction is mediated by the Ets and Gata domains. Co-expression of Gata2 augments Etv2 activity in promoting endothelial and hematopoietic lineage differentiation. Etv2 and Gata2 both bind the Spi1 promoter in vitro and in vivo. Co-immunoprecipitation, GST pulldown, ChIP, embryoid body differentiation Developmental biology High 24583263
2014 Etv2 binds to conserved Ets-binding sites in the Fli1 promoter and governs Fli1 expression. After Etv2 expression ceases at midgestation, Fli1 protein itself binds those same Ets-binding sites in a positive autoregulatory loop, maintaining Fli1 expression and selective Etv2-regulated endothelial genes. Fli1 also binds the Tie2 promoter/enhancer to control its expression beyond midgestation. ChIP, promoter binding assays, loss/gain-of-function, endothelial cell survival assays Circulation research High 24727028
2014 OVOL2, a C2H2 zinc finger protein, directly interacts with ER71/ETV2 in the nucleus. OVOL2 enhances ER71-mediated activation of the Flk1 promoter. Co-expression of ER71 and OVOL2 augmented FLK1+, endothelial, and hematopoietic cell generation from differentiating ESCs. Co-immunoprecipitation, luciferase reporter assay, ESC differentiation, shRNA knockdown Blood Medium 25267199
2014 ETV2 directly regulates Sox7 by binding ETV2 binding elements in the Sox7 upstream regulatory region and activating transcription. SOX7 overexpression mimics ETV2 in increasing endothelial progenitor cells, while Sox7 knockdown blocks ETV2-induced endothelial progenitor formation and angiogenic sprouting. ChIP, luciferase reporter assay, shRNA knockdown, embryoid body differentiation Stem cells and development Medium 24762086
2014 FoxC2 and Etv2 cooperatively activate a FOX:ETS composite motif in the ECE1 arterial enhancer. Additionally, Sox17 binds a conserved SOX site in the same enhancer, and the ECE1 enhancer is cooperatively activated by combinatorial action of FoxC2, Etv2, and Sox17. Transgenic mouse reporter assay, EMSA, promoter mutagenesis Developmental biology Medium 25179465
2015 ETV2 binds to enhancers that specify hematopoietic and endothelial cell lineages (global ChIP-seq). ETV2 activates other Ets genes (Fli1, Erg, etc.), establishing an ETS hierarchy, and the hematopoietic/endothelial program initiated by ETV2 is maintained by other ETS factors through an ETS switching mechanism. The hemangiogenic progenitor population (FLK1highPDGFRα-) is exclusively sensitive to ETV2-dependent FLK1 signaling. ChIP-seq, ESC differentiation, germ-line and conditional knockout mouse studies EMBO reports High 25802403
2015 Etv2 and Fli1b share the same transcriptional targets and bind to the same ETS sites, as shown by RNA-Seq and ChIP. Etv2 and Fli1b function redundantly during late vasculogenesis and early embryonic angiogenesis, with two distinct phases: Etv2 alone required for early vasculogenesis, Etv2 and Fli1b redundant during late vasculogenesis/early angiogenesis. Zebrafish mutants, RNA-Seq, ChIP, photoactivatable morpholinos, overexpression Arteriosclerosis, thrombosis, and vascular biology High 25722433
2015 Etv2 directly activates miR-130a. miR-130a promotes the endothelial program at the expense of cardiac program by directly suppressing Pdgfra expression and blocking Pdgfra signaling. CRISPR/Cas9 knockout of miR-130a reduced the endothelial program without affecting hematopoiesis. ChIP, CRISPR/Cas9 knockout, gain-of-function, Dicer ablation in Etv2-expressing cells, ESC/EB differentiation Cell reports High 26565905
2015 Endothelial ETV2 is required for injury-induced vascular regeneration. Etv2 expression is reactivated in endothelial cells after injury (but not detectable at steady-state). ETV2 upregulates Flk1/VEGFR2 expression after injury; Flk1 expression rescued angiogenesis defects in endothelial Etv2 conditional knockout mice. Etv2+/-;Flk1+/- double heterozygous mice showed more severe ischemic injury response, establishing epistatic interaction between ETV2 and FLK1. Endothelial-specific conditional knockout, ischemia models, lentiviral rescue, double heterozygous epistasis Arteriosclerosis, thrombosis, and vascular biology High 26586661
2015 LSD1/KDM1A promotes hematopoietic commitment of hemangioblasts through downregulation of Etv2. Hematopoietic defects in lsd1 mutant zebrafish were rescued by knockdown of etv2, placing LSD1 upstream of Etv2 in hemangioblast fate commitment. Zebrafish mutant screen, morpholino knockdown rescue, genetic epistasis Proceedings of the National Academy of Sciences of the United States of America Medium 26512114
2017 Vegf signaling promotes vascular endothelial differentiation by modulating Etv2 expression. Vegfr inhibition reduced etv2 expression; Vegfaa overexpression expanded etv2 expression. Vascular-specific overexpression of etv2 in Vegfr-inhibited embryos rescued defects in vascular endothelial differentiation, placing Etv2 downstream of Vegf signaling. Chemical Vegfr inhibition, genetic mutants, overexpression rescue, zebrafish embryos Developmental biology High 28279709
2017 ETV2 directly binds promoter region of Rhoj, serving as upstream transcriptional regulator of cell migration. ETV2 overexpression enhanced cell migration in ESCs, embryoid bodies, and fibroblasts; Etv2 knockout led to migratory defects of angioblasts in developing embryos. shRNA knockdown of Rhoj caused migration defects partially rescued by ETV2 overexpression. ChIP-seq, ATAC-seq, RNAseq, migration assays, Etv2 knockout embryos, shRNA knockdown rescue Arteriosclerosis, thrombosis, and vascular biology High 33115267
2017 IP3R-mediated Ca2+ signals govern hematopoietic versus cardiac fate of Flk1+ cells via the calcineurin-NFATc3-Etv2 pathway. Constitutively active NFATc3 rescued Etv2 expression in IP3R-knockout cells. NFATc3 directly targets Etv2 via an evolutionarily conserved cis-element. IP3R triple knockout ESCs, Ca2+ manipulation, calcineurin activation, NFATc3 constitutively active expression, ChIP Journal of molecular cell biology Medium 28419336
2017 Foxh1, in part through Eomes, is critical for FLK1+ mesoderm formation. Hemangiogenic fate is specified through a threshold-dependent mechanism in which VEGF-FLK1 signaling plays an instructive role by promoting Etv2 threshold expression. Genome-wide CRISPR screen, Brachyury/Etv2/Scl reporter ESC lines, transcriptome analysis Nature communications High 28912455
2018 ETV2 is sufficient and necessary for transdifferentiation of CD133+/Nestin+ GBM/neural stem cells to endothelial lineage. ChIP-Seq combined with gain-of-function RNA-Seq showed that ETV2 activates vascular genes and represses proneural genes to direct endo-transdifferentiation. This process is VEGF-A independent. ChIP-Seq, RNA-Seq, gain/loss-of-function experiments Signal transduction and targeted therapy Medium 29527330
2018 ETV2 directly binds promoter/enhancer regions of Vegfr3/Flt4 and lymphatic marker Lyve1, promoting their expression. Etv2 inhibition at 1 dpf inhibited lymphangiogenesis while blood vessel development was unaffected, and lymphatic progenitors failed to respond to Vegfc signaling in Etv2-deficient embryos. Photoactivatable morpholinos, ChIP-seq, luciferase reporter assays, zebrafish embryos Developmental biology High 29753018
2018 ETV2 directly interacts with TET1 and TET2 methylcytosine-converting enzymes. ETV2 binds ETS motifs in the Robo4 promoter and activates expression. ETV2-TET1/TET2 complexes demethylate the Robo4 promoter in non-endothelial cells, providing a mechanism for EC-specific gene expression via promoter demethylation. Co-immunoprecipitation, reporter assay, adenoviral expression, methylation analysis Scientific reports Medium 29618782
2019 cAMP/EPAC/RAP1 signaling facilitates ETV2-mediated endothelial transdifferentiation. ChIP-seq showed majority of ETV2 targets in human fibroblasts are related to vasculature development and Rap1 signaling. Activation of cAMP/EPAC/RAP1 axis improved efficiency and quality of ETV2-induced endothelial cells. ChIP-seq, pharmacological pathway activation, in vivo and in vitro functional assays Molecular therapy Medium 31864907
2019 ETV2 transcriptionally regulates Yes1 as a direct upstream regulator during embryogenesis. Doxycycline-mediated Etv2 induction increased Yes1 in a dose-dependent manner. Etv2 induction also caused ~2.5-fold increase in cellular proliferation, associated with upregulation of cell cycle genes E2f4 and Ccne1. ChIP-seq analysis, RNAseq, EdU-incorporation, doxycycline-inducible Etv2 ES/EB system, single-cell RNA-seq Scientific reports Medium 31278282
2019 ETV2/ER71 directly induces miR-126, which positively regulates FLK1+ cell generation by activating the MAPK pathway through targeting SPRED1. JUN/FOS activate the FLK1 enhancer through AP1 binding sequences downstream of this miR-126-MAPK axis. miRNA sequencing, ChIP-PCR, signaling pathway analysis Stem cell research & therapy Medium 31744543
2022 ETV2 functions as a pioneer factor that binds nucleosomal DNA and recruits BRG1. BRG1 recruitment remodels chromatin around endothelial genes and helps maintain an open configuration, resulting in increased H3K27ac deposition, thereby regulating endothelial development. Multi-omics (ATAC-seq, ChIP-seq), engineered ESC differentiation and reprogramming models, nucleosome binding assays Nature cell biology High 35550615
2022 ETV2 functions as a pioneer transcription factor initiating Shh expression during limb development by changing chromatin status of the ZRS limb enhancer. ETV2 binds nucleosome-occupied ZRS, causes nucleosomal displacement at ETS binding site clusters, and is antagonized by ETV4/5 repressors. Known human polydactyl mutations introduce novel ETV2 binding sites in the ZRS. Etv2 conditional inactivation, Etv2 overexpression in limb buds, ATAC-seq, ChIP-seq, luciferase reporter assays Nature communications High 35864091
2022 Etv2 dosage determines fate between hemogenic and aortic endothelium from a common hemogenic angioblast precursor. High Etv2 dosage specifies hemogenic endothelial cells while low Etv2 specifies conventional endothelium. Photoconvertible labeling, time-lapse imaging, single-cell RNA-sequencing, zebrafish Proceedings of the National Academy of Sciences of the United States of America Medium 35333649
2022 Etv2 functions directly in a coherent feedforward transcriptional network for vascular endothelial development. Low-level Etv2 expression is sufficient to induce and sustain the endothelial GRN, whereas a significantly higher threshold of Etv2 is required to initiate and sustain erythropoietic development. Etv2 induces the erythropoietic GRN indirectly via activation of Tal1. Hypomorphic Etv2 mutant analysis, gene regulatory network analysis Cell reports Medium 35649376
2022 Bmp signalling acts upstream of etv2 in regulating endocardial identity in zebrafish. Overactivation of Bmp signalling was unable to restore endocardial expression in etv2 mutants, but overexpression of etv2 rescued endocardial expression upon Bmp inhibition, establishing etv2 downstream of Bmp. Zebrafish etv2 and npas4l mutants, Bmp gain/loss of function, epistasis experiments Development (Cambridge, England) Medium 35531980
2023 ETV2 directly interacts with VEZF1 (vascular endothelial zinc finger 1), as demonstrated by yeast two-hybrid, co-immunoprecipitation, and GST pulldown. VEZF1 co-activates ETV2-dependent Flt1 promoter activity. VEZF1 binds the Flt1 promoter in vitro and in vivo (EMSA and ChIP). Yeast two-hybrid, co-immunoprecipitation, GST pulldown, luciferase reporter, EMSA, ChIP, Vezf1 knockout ESCs Frontiers in cell and developmental biology High 36923254
2023 ETV2 primes hematoendothelial gene enhancers prior to hematoendothelial fate commitment. ETV2 binding at hematoendothelial regulator genes precedes transcriptional activation; the shift from ETV2 binding to ETV2-bound enhancer activation drives hematoendothelial fate commitment. scRNA-seq, ATAC-seq, chromatin accessibility analysis of fate intermediates in mouse Cell reports Medium 37330911
2024 ETV2 interacts with KDM4A, an H3K9 demethylase; Etv2-null ESCs exhibit enhanced H3K9me3 levels at hematopoietic and endothelial genes. ETV2-mediated transcriptional activation of hematopoietic and endothelial genes depends on KDM4A histone demethylase activity. Cdh5Cre:Kdm4a;Etv2 double conditional knockout mice show more severe vascular regeneration defects than single knockouts. Co-immunoprecipitation, H3K9me3 ChIP, conditional double knockout mice, vascular perfusion assays iScience High 39811655
2024 BCL6B binds the promoter region of ETV2 and suppresses ETV2's transcriptional activity, thereby inhibiting endothelial cell differentiation from hiPSCs. ETV2 overexpression rescued the inhibitory effect of BCL6B overexpression on EC differentiation. Luciferase reporter assay, ChIP-PCR, doxycycline-inducible hiPSC systems, rescue experiments Stem cell research & therapy Medium 39075623
2025 ETV2 pioneer activity both directs EC specification and suppresses alternative fate acquisition. ETV2 recruits the transcriptional repressor REST to repress non-EC lineage genes. GABPA is identified as a cofactor essential for efficient EC specification downstream of ETV2. CUT&RUN, scRNA-seq, scATAC-seq, functional screening, candidate validation Nature cardiovascular research High 40495012
2017 Etv2 transcriptionally regulates miR-130a-Jarid2: Etv2-Cre Dicer ablation disrupts vascular patterning. miR-130a directly regulates Jarid2 expression by binding its 3'-UTR, promoting angiogenesis. Jarid2 overexpression leads to defective tube formation; miR-130a morpholino injection in zebrafish results in perturbed vascular patterning with increased Jarid2 levels. Etv2-Cre DicerL/L, miR-130a overexpression, Jarid2 3'UTR binding, zebrafish morpholinos, HUVEC tube formation PloS one Medium 29232705
2024 PPARγ transcriptionally activates the ETV2 promoter. Endothelial PPARγ overexpression increases ETV2 expression and endothelial markers, while PPARγ knockout decreases ETV2 expression. Etv2 haploinsufficient mice spontaneously developed pulmonary hypertension and right ventricular hypertrophy with increased EndoMT markers. Promoter reporter assay, conditional knockout/overexpression mouse models, EndoMT model Pulmonary circulation Medium 39391221

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 ER71 acts downstream of BMP, Notch, and Wnt signaling in blood and vessel progenitor specification. Cell stem cell 278 18462699
2014 ETS transcription factor ETV2 directly converts human fibroblasts into functional endothelial cells. Proceedings of the National Academy of Sciences of the United States of America 169 25540418
2011 Etv2/ER71 induces vascular mesoderm from Flk1+PDGFRα+ primitive mesoderm. Blood 146 21911838
2020 Robust differentiation of human pluripotent stem cells into endothelial cells via temporal modulation of ETV2 with modified mRNA. Science advances 115 32832668
2016 Direct Reprogramming of Human Dermal Fibroblasts Into Endothelial Cells Using ER71/ETV2. Circulation research 113 28003219
2008 Interplay among Etsrp/ER71, Scl, and Alk8 signaling controls endothelial and myeloid cell formation. Blood 99 18270322
2011 ER71 directs mesodermal fate decisions during embryogenesis. Development (Cambridge, England) 98 21989919
2015 Induction of hematopoietic and endothelial cell program orchestrated by ETS transcription factor ER71/ETV2. EMBO reports 94 25802403
2020 Generation of human endothelium in pig embryos deficient in ETV2. Nature biotechnology 85 32094659
2011 Vascular endothelial and endocardial progenitors differentiate as cardiomyocytes in the absence of Etsrp/Etv2 function. Development (Cambridge, England) 83 21989916
2012 ER71 specifies Flk-1+ hemangiogenic mesoderm by inhibiting cardiac mesoderm and Wnt signaling. Blood 71 22343916
2006 Repression of transcription by TSGA/Jmjd1a, a novel interaction partner of the ETS protein ER71. Journal of cellular biochemistry 65 16619273
2017 Vegf signaling promotes vascular endothelial differentiation by modulating etv2 expression. Developmental biology 55 28279709
2022 ETV2 functions as a pioneer factor to regulate and reprogram the endothelial lineage. Nature cell biology 51 35550615
2015 Etv2 and fli1b function together as key regulators of vasculogenesis and angiogenesis. Arteriosclerosis, thrombosis, and vascular biology 51 25722433
2015 Injury-Mediated Vascular Regeneration Requires Endothelial ER71/ETV2. Arteriosclerosis, thrombosis, and vascular biology 51 26586661
2014 Cooperative interaction of Etv2 and Gata2 regulates the development of endothelial and hematopoietic lineages. Developmental biology 51 24583263
2015 The ETS Factor, ETV2: a Master Regulator for Vascular Endothelial Cell Development. Molecules and cells 50 26694034
2012 The Flk1-Cre-mediated deletion of ETV2 defines its narrow temporal requirement during embryonic hematopoietic development. Stem cells (Dayton, Ohio) 48 22570122
2011 Etsrp/Etv2 is directly regulated by Foxc1a/b in the zebrafish angioblast. Circulation research 47 22135404
2013 Transdifferentiation of fast skeletal muscle into functional endothelium in vivo by transcription factor Etv2. PLoS biology 45 23853546
2010 ETS family protein ETV2 is required for initiation of the endothelial lineage but not the hematopoietic lineage in the Xenopus embryo. Developmental dynamics : an official publication of the American Association of Anatomists 44 20235229
2020 Single-cell transcriptomic analysis identifies the conversion of zebrafish Etv2-deficient vascular progenitors into skeletal muscle. Nature communications 41 32493965
2012 PKA/CREB signaling triggers initiation of endothelial and hematopoietic cell differentiation via Etv2 induction. Stem cells (Dayton, Ohio) 41 22267325
2014 Fli1 acts downstream of Etv2 to govern cell survival and vascular homeostasis via positive autoregulation. Circulation research 39 24727028
2015 LSD1/KDM1A promotes hematopoietic commitment of hemangioblasts through downregulation of Etv2. Proceedings of the National Academy of Sciences of the United States of America 38 26512114
2012 ETV2 expression marks blood and endothelium precursors, including hemogenic endothelium, at the onset of blood development. Developmental dynamics : an official publication of the American Association of Anatomists 38 22733530
2017 Embryonic Stem Cell Differentiation to Functional Arterial Endothelial Cells through Sequential Activation of ETV2 and NOTCH1 Signaling by HIF1α. Stem cell reports 36 28781077
2002 Functional analysis of the transcription factor ER71 and its activation of the matrix metalloproteinase-1 promoter. Nucleic acids research 36 12087183
2018 ETV2 mediates endothelial transdifferentiation of glioblastoma. Signal transduction and targeted therapy 33 29527330
2017 Adventitial Sca1+ Cells Transduced With ETV2 Are Committed to the Endothelial Fate and Improve Vascular Remodeling After Injury. Arteriosclerosis, thrombosis, and vascular biology 32 29191922
2012 Transcription factors ER71/ETV2 and SOX9 participate in a positive feedback loop in fetal and adult mouse testis. The Journal of biological chemistry 32 22613723
2016 ETS Transcription Factor ETV2/ER71/Etsrp in Hematopoietic and Vascular Development. Current topics in developmental biology 31 27137655
2012 Endothelialization and altered hematopoiesis by persistent Etv2 expression in mice. Experimental hematology 31 22659386
2005 Cloning of the murine ER71 gene (Etsrp71) and initial characterization of its promoter. Genomics 30 15780752
2017 Dpath software reveals hierarchical haemato-endothelial lineages of Etv2 progenitors based on single-cell transcriptome analysis. Nature communications 28 28181481
2017 A CRISPR screen identifies genes controlling Etv2 threshold expression in murine hemangiogenic fate commitment. Nature communications 28 28912455
2014 An arterial-specific enhancer of the human endothelin converting enzyme 1 (ECE1) gene is synergistically activated by Sox17, FoxC2, and Etv2. Developmental biology 27 25179465
2013 Post-transcriptional mechanisms contribute to Etv2 repression during vascular development. Developmental biology 27 24036310
2011 The Er71 is an important regulator of hematopoietic stem cells in adult mice. Stem cells (Dayton, Ohio) 27 21425416
2018 ETV2-TET1/TET2 Complexes Induce Endothelial Cell-Specific Robo4 Expression via Promoter Demethylation. Scientific reports 26 29618782
2014 Sox7 is regulated by ETV2 during cardiovascular development. Stem cells and development 26 24762086
2017 ETS transcription factors Etv2 and Fli1b are required for tumor angiogenesis. Angiogenesis 25 28108843
2015 ETV2 expression increases the efficiency of primitive endothelial cell derivation from human embryonic stem cells. Cell regeneration (London, England) 25 25780560
2014 OVOL2 is a critical regulator of ER71/ETV2 in generating FLK1+, hematopoietic, and endothelial cells from embryonic stem cells. Blood 25 25267199
2019 In vivo transduction of ETV2 improves cardiac function and induces vascular regeneration following myocardial infarction. Experimental & molecular medicine 23 30755583
2017 ETV2/ER71 regulates hematopoietic regeneration by promoting hematopoietic stem cell proliferation. The Journal of experimental medicine 23 28461595
2016 Etv2 IS A MASTER REGULATOR OF HEMATOENDOTHELIAL LINEAGES. Transactions of the American Clinical and Climatological Association 23 28066054
2021 Upregulation of ETV2 Expression Promotes Endothelial Differentiation of Human Dental Pulp Stem Cells. Cell transplantation 22 33522307
2020 Ets1 functions partially redundantly with Etv2 to promote embryonic vasculogenesis and angiogenesis in zebrafish. Developmental biology 22 32628937
2019 cAMP/EPAC Signaling Enables ETV2 to Induce Endothelial Cells with High Angiogenesis Potential. Molecular therapy : the journal of the American Society of Gene Therapy 22 31864907
2022 ETV2 promotes osteogenic differentiation of human dental pulp stem cells through the ERK/MAPK and PI3K-Akt signaling pathways. Stem cell research & therapy 21 36195958
2023 ETV2/ER71, the key factor leading the paths to vascular regeneration and angiogenic reprogramming. Stem cell research & therapy 20 36927793
2017 IP3R-mediated Ca2+ signals govern hematopoietic and cardiac divergence of Flk1+ cells via the calcineurin-NFATc3-Etv2 pathway. Journal of molecular cell biology 20 28419336
2016 Significant improvement of direct reprogramming efficacy of fibroblasts into progenitor endothelial cells by ETV2 and hypoxia. Stem cell research & therapy 20 27488544
2015 The Etv2-miR-130a Network Regulates Mesodermal Specification. Cell reports 20 26565905
2013 Etv2 rescues Flk1 mutant embryoid bodies. Genesis (New York, N.Y. : 2000) 20 23606617
2018 Requisite endothelial reactivation and effective siRNA nanoparticle targeting of Etv2/Er71 in tumor angiogenesis. JCI insight 19 29669933
2022 Hemogenic and aortic endothelium arise from a common hemogenic angioblast precursor and are specified by the Etv2 dosage. Proceedings of the National Academy of Sciences of the United States of America 17 35333649
2022 Differential Etv2 threshold requirement for endothelial and erythropoietic development. Cell reports 17 35649376
2020 ETV2 (Ets Variant Transcription Factor 2)-Rhoj Cascade Regulates Endothelial Progenitor Cell Migration During Embryogenesis. Arteriosclerosis, thrombosis, and vascular biology 17 33115267
2017 Etv2-miR-130a-Jarid2 cascade regulates vascular patterning during embryogenesis. PloS one 17 29232705
2022 Transient ETV2 Expression Promotes the Generation of Mature Endothelial Cells from Human Pluripotent Stem Cells. Biological & pharmaceutical bulletin 16 35370273
2022 Etv2 regulates enhancer chromatin status to initiate Shh expression in the limb bud. Nature communications 15 35864091
2019 ETV2/ER71 Transcription Factor as a Therapeutic Vehicle for Cardiovascular Disease. Theranostics 15 31534512
2018 ETS transcription factor Etsrp / Etv2 is required for lymphangiogenesis and directly regulates vegfr3 / flt4 expression. Developmental biology 15 29753018
2024 A streamlined method to generate endothelial cells from human pluripotent stem cells via transient doxycycline-inducible ETV2 activation. Angiogenesis 14 38969874
2014 Transcriptional inhibition of etv2 expression is essential for embryonic cardiac development. Developmental biology 14 24984259
2023 ETV2 and VEZF1 interaction and regulation of the hematoendothelial lineage during embryogenesis. Frontiers in cell and developmental biology 12 36923254
2019 Etv2 transcriptionally regulates Yes1 and promotes cell proliferation during embryogenesis. Scientific reports 12 31278282
2019 ETV2/ER71 regulates the generation of FLK1+ cells from mouse embryonic stem cells through miR-126-MAPK signaling. Stem cell research & therapy 12 31744543
2014 Distinct regulation of the anterior and posterior myeloperoxidase expression by Etv2 and Gata1 during primitive Granulopoiesis in zebrafish. Developmental biology 11 24956419
2019 Zebrafish etv2 knock-in line labels vascular endothelial and blood progenitor cells. Developmental dynamics : an official publication of the American Association of Anatomists 10 31705559
2023 ETV2 primes hematoendothelial gene enhancers prior to hematoendothelial fate commitment. Cell reports 9 37330911
2021 ER71/ETV2 Promotes Hair Regeneration from Chemotherapeutic Drug-Induced Hair Loss by Enhancing Angiogenesis. Biomolecules & therapeutics 9 33814416
2019 Clec14a genetically interacts with Etv2 and Vegf signaling during vasculogenesis and angiogenesis in zebrafish. BMC developmental biology 9 30953479
2017 ETV-2 activated proliferation of endothelial cells and attenuated acute hindlimb ischemia in mice. In vitro cellular & developmental biology. Animal 8 28424975
2024 BCL6B-dependent suppression of ETV2 hampers endothelial cell differentiation. Stem cell research & therapy 7 39075623
2021 Biallelic variants in ETV2 in a family with congenital heart defects, vertebral abnormalities and preaxial polydactyly. European journal of medical genetics 7 33359164
2025 Pioneer factor ETV2 safeguards endothelial cell specification by recruiting the repressor REST to restrict alternative lineage commitment. Nature cardiovascular research 6 40495012
2024 SOX17/ETV2 improves the direct reprogramming of adult fibroblasts to endothelial cells. Cell reports methods 6 38503291
2022 Endocardial identity is established during early somitogenesis by Bmp signalling acting upstream of npas4l and etv2. Development (Cambridge, England) 6 35531980
2020 Etv2- and Fli1-Induced Vascular Progenitor Cells Enhance Functional Recovery in Ischemic Vascular Disease Model-Brief Report. Arteriosclerosis, thrombosis, and vascular biology 6 32075417
2017 ETS transcription factor ETV2/ER71/Etsrp in hematopoietic and vascular development, injury, and regeneration. Developmental dynamics : an official publication of the American Association of Anatomists 6 28026128
2025 ETV2 Overexpression Promotes Efficient Differentiation of Pluripotent Stem Cells to Endothelial Cells. Biotechnology and bioengineering 5 40134129
2023 ETV2 Enhances CXCL5 Secretion from Endothelial Cells, Leading to the Promotion of Vascular Smooth Muscle Cell Migration. International journal of molecular sciences 5 37373052
2020 FGF primes angioblast formation by inducing ETV2 and LMO2 via FGFR1/BRAF/MEK/ERK. Cellular and molecular life sciences : CMLS 5 32910224
2017 Extracellular vesicles of ETV2 transfected fibroblasts stimulate endothelial cells and improve neovascularization in a murine model of hindlimb ischemia. Cytotechnology 5 28466428
2013 Role of Etv2-positive cells in the remodeling morphogenesis during vascular development. Genes to cells : devoted to molecular & cellular mechanisms 5 23795570
2023 ETV2 Upregulation Marks the Specification of Early Cardiomyocytes and Endothelial Cells During Co-differentiation. Stem cells (Dayton, Ohio) 4 36512477
2022 ETV2 regulates PARP-1 binding protein to induce ER stress-mediated death in tuberin-deficient cells. Life science alliance 4 35181635
2022 Generation of a doxycycline-inducible ETV2 expression cell line using PiggyBac transposase system. Stem cell research 4 36463633
2022 One-Step In Vitro Generation of ETV2-Null Pig Embryos. Animals : an open access journal from MDPI 3 35883376
2018 ETS transcription factor ETV2/ER71/Etsrp in haematopoietic regeneration. Current opinion in hematology 3 29697486
2025 APPswe mutation causes functional deficits in endothelial cells generated by transient ETV2 overexpression in human iPSCs. Fluids and barriers of the CNS 2 41272813
2024 PPARγ/ETV2 axis regulates endothelial-to-mesenchymal transition in pulmonary hypertension. Pulmonary circulation 2 39391221
2024 ETV2/ER71 regulates hematovascular lineage generation and vascularization through an H3K9 demethylase, KDM4A. iScience 2 39811655
2022 Gfi1aa/Lsd1 Facilitates Hemangioblast Differentiation Into Primitive Erythrocytes by Targeting etv2 and sox7 in Zebrafish. Frontiers in cell and developmental biology 2 35096818
2021 Morphological characterization of Etv2 vascular explants using fractal analysis and atomic force microscopy. Microvascular research 2 34146583
2020 ETV2-null porcine embryos survive to post-implantation following incomplete enucleation. Reproduction (Cambridge, England) 2 31990674

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