Affinage

EPAS1

Endothelial PAS domain-containing protein 1 · UniProt Q99814

Length
870 aa
Mass
96.5 kDa
Annotated
2026-06-09
100 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EPAS1 (HIF-2α) is an oxygen-regulated bHLH-PAS transcription factor that heterodimerizes with ARNT/HIF-1β to bind the hypoxia response element and activate target genes under hypoxia, functioning as a master regulator of erythropoiesis, vascular biology, and tissue-specific adaptive responses (PMID:9000051). It executes a target gene program that is partly distinct from HIF-1α, conferring isoform-selective control of erythropoietin (EPO), where cis-acting elements in the complete EPO enhancer specify HIF-2α dependence (PMID:15240563), as well as selective induction of VEGF (PMID:11301389), Tie-2 (PMID:9000051), Runx2 (PMID:18442887), and, in endothelium, the pro-thrombotic downregulation of tissue factor pathway inhibitor (PMID:26826018). EPAS1 protein stability is the central control node: gain-of-function missense mutations near the Pro531 hydroxylation site (G537W, D539E, A530V) escape PHD2/VHL-mediated oxygen-dependent degradation, stabilizing the protein and causing erythrocytosis, pulmonary hypertension, vascular malformations, and pheochromocytoma/paraganglioma (PMID:18184961, PMID:20007141, PMID:23533246, PMID:23640890, PMID:33497361, PMID:33796838). Stability is further tuned by HAT1-mediated acetylation at K512/K596 (PMID:36410688), and EPAS1 itself can be cleared through autophagic/lysosomal degradation (PMID:39477683). Through cell-type-specific transcriptional programs, EPAS1 maintains Sertoli cell tight junctions and the blood-testis barrier (PMID:20181618), promotes satellite cell quiescence via Spry1 (PMID:29533927), protects the glomerular filtration barrier and the endothelium against atherosclerosis through CD36/LIPG-driven fatty acid oxidation (PMID:28928136, PMID:39234692), drives retinal and developmental vascular remodeling via VEGF/EPO/endostatin (PMID:29615467, PMID:33497361), promotes orbital fibrosis via LOX (PMID:30388216), and induces IL-31-driven atopic inflammation in T cells through an ARNT-independent, SP1-dependent mechanism downstream of DOCK8 (PMID:28067314). Beyond canonical hypoxia signaling, EPAS1 forms a non-canonical heterodimer with the circadian factor BMAL1, resolved by cryo-EM, that drives rhythmic AREG expression and modulates circadian variation in myocardial injury (PMID:40269168, PMID:35584682). Hypomorphic regulatory and coding EPAS1 variants enriched in high-altitude Tibetan and Andean populations blunt the erythrocytotic and pulmonary vascular responses to chronic hypoxia (PMID:28096303, PMID:38335297, PMID:37463421).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1997 High

    Established the molecular identity of EPAS1 as a hypoxia-inducible bHLH-PAS transcription factor, defining its DNA target and obligate dimerization partner.

    Evidence Cloning, HRE DNA-binding, reporter transactivation and ARNT heterodimer characterization; selective Tie-2 activation in endothelial cells

    PMID:9000051

    Open questions at the time
    • Did not define which targets are HIF-2α-specific versus shared with HIF-1α
    • No structural model of the DNA-bound complex
  2. 1999 Medium

    Showed that EPAS1 transactivation is gated by upstream signaling, placing calmodulin and p42/p44 MAPK in the hypoxia-response pathway.

    Evidence MEK inhibitor, dominant-active MEK1, calmodulin antagonists and reporter/phosphorylation assays in PC12 cells; expression mapping in chicken embryo

    PMID:10559262 PMID:10580084

    Open questions at the time
    • Phosphorylation sites on EPAS1 not mapped
    • Connection to oxygen sensing not integrated
    • Single-lab pharmacology
  3. 2003 High

    Defined EPAS1's role in erythropoiesis as a non-cell-autonomous niche function rather than intrinsic to hematopoietic cells.

    Evidence Constitutive knockout mouse with pancytopenia plus bone marrow reconstitution epistasis

    PMID:12750163

    Open questions at the time
    • Niche cell type responsible not identified
    • Molecular effector in the microenvironment unresolved
  4. 2004 High

    Resolved the long-standing HIF-1α vs HIF-2α specificity question for EPO, showing EPO induction is HIF-2α-dependent and encoded by cis-elements beyond the core HRE.

    Evidence siRNA discrimination of HIF-1α vs HIF-2α with reporter and target-gene panels in multiple cell lines; adipogenic gain/loss-of-function in 3T3 cells

    PMID:15240563 PMID:15258146

    Open questions at the time
    • Identity of the EPO enhancer cofactors conferring selectivity not defined
    • Adipogenesis role not confirmed in vivo
  5. 2008 High

    Linked EPAS1 dysregulation to human disease by identifying a stabilizing gain-of-function mutation causing familial erythrocytosis, and extended direct target binding to Runx2.

    Evidence Family sequencing with protein stability/HIF activity assays (G537W); reporter screen, EMSA, ChIP and siRNA for Runx2 promoter

    PMID:18184961 PMID:18442887

    Open questions at the time
    • Did not yet establish causality in an animal model
    • Tissue specificity of Runx2 regulation unaddressed
  6. 2010 Medium

    Mechanistically dissected how erythrocytosis mutations evade degradation by mapping impaired PHD2 and VHL binding adjacent to the hydroxylation site.

    Evidence Functional protein interaction assays for the D539E variant with PHD2 and VHL

    PMID:20007141

    Open questions at the time
    • Single-lab biochemistry without structural detail
    • Quantitative contribution of each contact unresolved
  7. 2013 High

    Genetically validated EPAS1 missense mutations as causal for erythrocytosis and pulmonary hypertension, and extended the stabilization mechanism to sporadic neuroendocrine tumors.

    Evidence G536W knock-in mouse with dose-dependent erythrocytosis/pulmonary hypertension; somatic mutant expression with stability/target-gene readouts and xenografts in pheochromocytoma/paraganglioma

    PMID:23533246 PMID:23640890

    Open questions at the time
    • Downstream effectors driving pulmonary vascular phenotype not yet identified
    • Chromaffin differentiation block mechanism unresolved
  8. 2011 High

    Revealed a developmental, non-erythroid requirement for EPAS1 in maintaining the blood-testis barrier.

    Evidence Conditional knockout with histology and immunofluorescence of TJP1/TJP2/occludin in Sertoli cells

    PMID:20181618

    Open questions at the time
    • Whether tight junction genes are direct EPAS1 targets not shown
    • Hypoxia-dependence in this context untested
  9. 2016 Medium

    Expanded EPAS1 regulatory inputs to include epigenetic promoter control and defined a hypoxia-specific endothelial pro-thrombotic output.

    Evidence MBD3 ChIP/methylation/shRNA at the EPAS1 promoter; HIF-2α-selective siRNA with TFPI/FXa coagulation assays in endothelial cells

    PMID:26826018 PMID:27465550

    Open questions at the time
    • MBD3 demethylation mechanism at EPAS1 promoter unresolved
    • TFPI regulation single-lab without in vivo confirmation
  10. 2015 Medium

    Established transcriptional and signaling control of EPAS1 mRNA abundance itself, and uncovered a HIF-2α-specific organellar autophagy function.

    Evidence PI3K/mTORC2 inhibitors and ERRα knockdown with actinomycin chase defining transcriptional regulation of HIF2A mRNA; loss-of-function pexophagy assays in hepatocytes

    PMID:25912138 PMID:25997392 PMID:26432405

    Open questions at the time
    • Mechanism linking mTORC2/ERRα to HIF2A promoter unknown
    • Pexophagy effectors not defined
  11. 2017 High

    Demonstrated an ARNT-independent EPAS1 transcriptional program in immunity and a regulatory variant basis for high-altitude adaptation.

    Evidence Conditional T-cell knockout, Il31 promoter reporter, DOCK8 co-IP/nuclear translocation; Tibetan noncoding-variant reporters, tissue qRT-PCR and heterozygous KO mouse hypoxia challenge

    PMID:28067314 PMID:28096303

    Open questions at the time
    • How SP1 substitutes for ARNT at the Il31 promoter mechanistically unresolved
    • Causal Tibetan variant(s) among linked haplotype not pinpointed
  12. 2018 High

    Defined direct cell-fate roles of EPAS1 via specific target promoters in muscle stem cells and retinal angiogenesis, plus a self-limiting methylation feedback loop.

    Evidence Satellite-cell conditional KO with Spry1 ChIP and pharmacological inhibition; retinal neuroprogenitor Cre-lox KO affecting VEGF/EPO/endostatin; DNMT1 ChIP and bisulfite analysis in NSCLC

    PMID:29533927 PMID:29615467 PMID:29920222

    Open questions at the time
    • Whether the DNMT1 feedback loop operates in normal tissues unknown
    • Quiescence vs proliferation switch upstream of EPAS1 unresolved
  13. 2019 Medium

    Identified EPAS1-driven fibrosis via LOX and an unconventional cell-type-specific PHD3 mechanism that stabilizes HIF2A mRNA.

    Evidence Orbital fibroblast organoids with HIF2A/LOX gain/loss-of-function; siRNA PHD-panel with mRNA stability assays in ccRCC; Tibetan horse mutagenesis (stability/ARNT affinity)

    PMID:30388216 PMID:30617181 PMID:31273382

    Open questions at the time
    • Direct demonstration of PHD3 acting on HIF2A mRNA lacking
    • LOX as direct vs indirect target not fully resolved
  14. 2021 High

    Established EPAS1 in vascular development and remodeling and linked gain-of-function to smooth muscle pathology and the glomerular barrier.

    Evidence Epas1-A529V transgenic mouse imaging of failed vessel regression; G537W knock-in iPSC SMCs with EDN1 axis and matching GOF mice; endothelial-specific KO in angiotensin-II hypertension

    PMID:28928136 PMID:33497361 PMID:33796838

    Open questions at the time
    • Mechanism of EPAS1 control over developmental vessel regression unresolved
    • Endothelial glomerular-protective effector not identified
  15. 2022 High

    Defined post-translational acetylation control of EPAS1 stability and a non-canonical circadian partnership, plus a pleiotropic cis-regulatory enhancer.

    Evidence HAT1 co-IP and K512/K596 acetyl-mimic rescue; pika Epas1-Bmal1 complex at the Per2 promoter with knock-in mice; ENH5 CRISPR deletion with RNA-seq in cells and mice

    PMID:35584682 PMID:36410688 PMID:36417539

    Open questions at the time
    • Physiological signals controlling HAT1-EPAS1 acetylation unknown
    • Direct ENH5–EPAS1 promoter contact not mapped
  16. 2024 High

    Resolved the BMAL1-HIF2A complex structurally and tied it to circadian cardiac injury, defined an endothelial-protective fatty-acid-oxidation program, and mechanistically validated Andean adaptive variants.

    Evidence Cryo-EM of BMAL1-HIF2A-DNA with ChIP/KO/pharmacology for AREG; endothelial Epas1 KO atherosclerosis model with CD36/LIPG/FAO; H194R base-edited cells and knock-in mice; ATP6V0D2-driven autophagic EPAS1 degradation

    PMID:37463421 PMID:38335297 PMID:39234692 PMID:39477683 PMID:40269168

    Open questions at the time
    • How diurnal cues switch between ARNT and BMAL1 partnering unresolved
    • In vivo relevance of ATP6V0D2 degradation pathway beyond xenografts unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How EPAS1 integrates its multiple control layers — oxygen-dependent hydroxylation, acetylation, mRNA-level regulation, partner choice (ARNT vs BMAL1 vs SP1), and tissue-specific cofactors — into context-appropriate target selection remains unresolved.
  • No unified model of partner/cofactor selection across cell types
  • Determinants of HIF-2α-specific enhancer engagement only partially defined
  • Cross-talk between circadian and hypoxic regulatory modes unmapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 2 GO:0005654 nucleoplasm 2
Pathway
R-HSA-1643685 Disease 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-9612973 Autophagy 2 R-HSA-9909396 Circadian clock 2
Partners
ARNTBMAL1DOCK8HAT1MBD3PHD2SP1VHL
Complex memberships
BMAL1-HIF2A heterodimerEPAS1-ARNT (HIF-2) heterodimer

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 EPAS1 (HIF-2α) was cloned and characterized as a bHLH-PAS domain transcription factor that binds the HIF hypoxia response element (5'-GCCCTACGTGCTGTCTCA-3') derived from the erythropoietin gene, activates transcription under hypoxic conditions, and forms a heterodimeric complex with ARNT (aryl hydrocarbon receptor nuclear translocator/HIF-1β) prior to transcriptional activation of target genes. Cloning, DNA binding assay, reporter gene (transcriptional activation), co-immunoprecipitation/heterodimer characterization Genes & development High 9000051
1997 EPAS1 selectively activates transcription of the endothelial tyrosine kinase gene Tie-2, demonstrating cell-type-specific target gene regulation beyond HIF-1α. Reporter gene assay / transcriptional activation in endothelial cells Genes & development Medium 9000051
1999 EPAS1 trans-activation of hypoxia response element (HRE) reporter genes during hypoxia requires p42/p44 MAPK (ERK) signaling: MEK inhibitor PD98059 completely blocked hypoxia-induced HRE transactivation by EPAS1, and constitutively active MEK1 mimicked hypoxia. EPAS1 phosphorylation under hypoxia was MAPK-independent. Both MAPK activation and EPAS1 trans-activation were sensitive to calmodulin antagonists, placing calmodulin upstream of MAPK in this pathway, and were Ras-independent. Pharmacological inhibition (MEK inhibitor PD98059, calmodulin antagonists), dominant-active kinase expression, luciferase reporter assay, phosphorylation analysis in PC12 cells The Journal of biological chemistry Medium 10559262
1999 Chicken EPAS1 is expressed in endothelial cells, vascular smooth muscle cells, liver, kidney, and sympathetic nervous system cells, where it co-localizes with its putative target gene tyrosine hydroxylase, consistent with a role in catecholamine synthesis regulation. Cloning of chicken EPAS1 ortholog, in situ hybridization / immunohistochemistry co-localization in embryo FEBS letters Medium 10580084
2001 EPAS1 up-regulates endogenous VEGF transcription (mRNA and protein) when expressed in 293 Tet-Off cells, and this induction is reversed by doxycycline-mediated suppression of EPAS1; transferrin receptor (a HIF-1α target) was not affected, indicating selectivity. Tet-Off inducible expression system, RT-PCR, ELISA Cancer Medium 11301389
2003 Global knockout of EPAS1/HIF-2α in adult mice results in pancytopenia; bone marrow reconstitution experiments established that the hematopoietic defect is due to loss of EPAS1 in the bone marrow microenvironment (niche), not intrinsic to hematopoietic cells. Constitutive knockout mouse, bone marrow transplantation / reconstitution Blood High 12750163
2004 RNAi knockdown showed that erythropoietin (EPO) gene induction under hypoxia is dependent specifically on HIF-2α (EPAS1), not HIF-1α, in Hep3B and Kelly cells. Most other HRE-driven target genes tested were HIF-1α-dependent. The complete EPO enhancer (but not a minimal EPO-HRE reporter) confers HIF-2α specificity, indicating cis-acting elements beyond the core HRE specify isoform selectivity. siRNA knockdown of HIF-1α vs HIF-2α, luciferase reporter assay with EPO HRE and complete enhancer, RT-PCR for target genes FASEB journal High 15240563
2004 EPAS1 promotes adipogenesis: a dominant-negative C-terminal deletion mutant of EPAS1 blocked lipid accumulation and adipogenic gene expression (PPARγ2, aP2) in 3T3-L1 cells, while EPAS1 overexpression promoted adipogenesis in NIH 3T3 cells. EPAS1 transcriptionally regulates GLUT1, GLUT4, and IRS3, controlling glucose transport in adipocytes. Inducible dominant-negative expression, adenoviral overexpression, RT-PCR, glucose transport assay in 3T3-L1 and NIH 3T3 cells The Journal of biological chemistry Medium 15258146
2008 HIF2A identified as the strongest transcriptional activator of the Runx2-P1 promoter in a screen of 100 transcription factors; a HIF2A-responsive site was mapped to -106 to -104 bp of the Runx2 promoter by mutation analysis; EMSA and ChIP confirmed direct HIF2A binding to this promoter in vitro and in vivo; siRNA knockdown of HIF2A decreased Runx2 expression. Luciferase reporter screen of 100 TFs, deletion/mutation analysis, EMSA, ChIP, siRNA knockdown Gene High 18442887
2008 A HIF2A missense mutation (Gly537Trp) in exon 12 causes familial erythrocytosis by stabilizing HIF-2α protein, functionally impairing its regulation by the PHD/VHL oxygen-sensing pathway and leading to increased EPO production. Mutation identification by Sanger sequencing, functional studies of protein stability and HIF activity The New England journal of medicine High 18184961
2009 The erythrocytosis-associated HIF2A mutation p.Asp539Glu (located C-terminal to the primary hydroxylation site Pro531) compromises binding of HIF-2α to both PHD2 and VHL, thus impairing oxygen-dependent degradation. Mutation functional analysis, protein binding assay (HIF-2α interaction with PHD2 and VHL) Haematologica Medium 20007141
2010 EPAS1 is required for postnatal spermatogenesis in mice: conditional ablation of Epas1 causes male infertility through defective Sertoli cell tight junction formation, disrupting the blood-testis barrier. Epas1-null Sertoli cells show decreased expression of tight junction proteins TJP1 (ZO-1), TJP2 (ZO-2), and occludin, and Epas1-null testes display disrupted basement membranes leading to premature germ cell release. Conditional knockout mouse (Cre-lox), histology, immunofluorescence of tight junction proteins Biology of reproduction High 20181618
2013 Somatic HIF2A mutations in pheochromocytoma/paraganglioma tumor cells confer increased HIF-2α protein stability, resistance to VHL-mediated degradation, and enhanced transcription of HIF-2α target genes; ectopic expression of mutant HIF2A in cell lines (HEK293, 786-0, PC12) increased stability and reduced chromaffin cell differentiation; mice injected with mutant-HIF2A-expressing cells developed tumors with shorter latency than wild-type. Ectopic expression of mutant HIF2A, protein stability assay, target gene induction, xenograft mouse model Endocrine-related cancer High 23533246
2013 A mouse model bearing the G536W missense mutation in Hif2a (corresponding to human G537W erythrocytosis mutation) displays dose-dependent erythrocytosis and pulmonary hypertension, firmly establishing HIF-2α missense mutations as causal for erythrocytosis and implicating HIF-2α dysregulation in pulmonary vascular phenotypes. Knock-in mouse model (heterozygous and homozygous), phenotypic characterization (hematocrit, pulmonary pressure) The Journal of biological chemistry High 23640890
2015 EPAS1/HIF-2α drives pexophagy (peroxisome autophagy) in hepatocytes, representing a unique function distinct from HIF-1α. Loss-of-function in hepatocytes, peroxisome quantification, autophagy assay Autophagy Medium 25997392
2015 HIF-2α transcriptional regulation of HIF2A mRNA in neuroblastoma is controlled by the PI3K-mTORC2 signaling axis (not Akt or mTORC1): pharmacological inhibition of PI3K or mTORC2, but not mTORC1, reduced HIF2A mRNA and protein levels, and was associated with smaller, less vascularized tumors in vivo. PI3K/mTOR inhibitors, siRNA knockdown, xenograft mouse model, mRNA/protein quantification Cancer research Medium 26432405
2016 EPAS1/HIF-2α mediates downregulation of tissue factor pathway inhibitor (TFPI) under hypoxia in human endothelial cells, leading to increased factor Xa activity on the cell surface and a pro-thrombotic state. The effect was specific to HIF-2α (not HIF-1α) based on selective knockdown. Chemical and 1% O2 hypoxia induction, selective HIF-2α siRNA, qRT-PCR, ELISA, Western blot, FXa chromogenic activity assay Biochimica et biophysica acta Medium 26826018
2017 EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction in CD4+ T cells. EPAS1-mediated Il31 promoter activation is independent of its canonical partner ARNT but requires SP1. DOCK8 acts as an adaptor/negative regulator of EPAS1 nuclear translocation; in its absence, EPAS1 accumulates in the nucleus and drives IL-31 expression. Conditional EPAS1 knockout in CD4+ T cells, Il31 promoter reporter assay, nuclear translocation assay, co-immunoprecipitation (DOCK8-EPAS1 interaction) Nature communications High 28067314
2017 Tibetan-enriched noncoding EPAS1 variants down-regulate EPAS1 expression in human umbilical endothelial cells and placentas. Heterozygous EPAS1 knockout mice display blunted physiological responses to chronic hypoxia (reduced hemoglobin increase, low pulmonary vasoconstriction), mirroring the Tibetan phenotype. Luciferase reporter assay for variant effects on expression, qRT-PCR in human tissues, heterozygous knockout mouse with hypoxia challenge Molecular biology and evolution High 28096303
2018 HIF2A promotes the quiescence, self-renewal, and long-term maintenance of skeletal muscle satellite cells by binding the Spry1 gene promoter and activating Spry1 expression, which suppresses myogenic differentiation. HIF2A ablation depletes satellite cells and impairs long-term muscle regeneration; transient pharmacological inhibition of HIF2A accelerates regeneration by increasing satellite cell proliferation and differentiation. Satellite cell-specific conditional knockout, HIF2A stabilization under normoxia, chromatin immunoprecipitation (HIF2A binding to Spry1 promoter), pharmacological HIF2A inhibition, engraftment assay The Journal of clinical investigation High 29533927
2018 EPAS1/HIF-2α is stabilized under hypoxia and transactivates DNMT1 expression (confirmed by ChIP assay), leading to hypermethylation of the EPAS1 promoter and decreased EPAS1 mRNA—a negative feedback loop in non-small cell lung cancer. ChIP assay for EPAS1 binding to DNMT1 promoter, bisulfite sequencing/methylation analysis, demethylation rescue experiments, qRT-PCR FASEB journal Medium 29920222
2019 HIF-2α (EPAS1) drives fibrotic tissue remodeling in thyroid-associated orbitopathy via a HIF2A→LOX (lysyl oxidase) pathway: HIF2A (but not HIF1A) induces LOX expression, promoting collagen cross-linking and ECM deposition in orbital fibroblast 3D organoids. shRNA or small-molecule inhibition of HIF2A or LOX ameliorated fibrosis; constitutively active HIF2A was sufficient to initiate LOX-dependent fibrotic remodeling. 3D organoid culture of orbital fibroblasts, shRNA knockdown, small-molecule inhibitors, constitutively active HIF2A overexpression, LOX activity assay Endocrinology High 30388216
2019 PHD3 maintains high HIF2A mRNA levels in clear cell renal cell carcinoma (ccRCC) through regulation of HIF2A mRNA stability. Unlike canonical PHD3 function (protein hydroxylation/degradation), PHD3 knockdown in ccRCC cells specifically decreased HIF2A mRNA and protein, whereas PHD3 knockdown in non-RCC cells increased HIF-2α protein. The effect was attributed to mRNA stability, not transcription. siRNA knockdown of PHD family members, immunoblot, immunofluorescence, qRT-PCR, mRNA stability assay, forced HIF2A rescue expression The Journal of biological chemistry Medium 30617181
2019 EPAS1 missense mutations in Tibetan horses increase EPAS1 protein stability and its heterodimerization affinity to ARNT (HIF1B), demonstrated by protein mutagenesis functional validation. Protein mutagenesis, stability and heterodimerization assay Molecular biology and evolution Medium 31273382
2021 Endothelial-specific Epas1 knockout in mice subjected to angiotensin II-induced hypertension results in worsened albuminuria, podocyte lesions, parietal epithelial cell activation, and FSGS—despite identical blood pressure—establishing that endothelial EPAS1 has a protective role in the glomerular filtration barrier during hypertensive injury. Endothelial-selective conditional Epas1 knockout mouse, angiotensin II infusion, renal histology, albuminuria measurement Journal of the American Society of Nephrology High 28928136
2022 HAT1 (histone acetyltransferase 1) directly interacts with HIF2A (EPAS1) and acetylates it at K512 and K596 residues, stabilizing HIF2A protein under both normoxia and hypoxia. Acetylation-mimic mutations at either residue (K512Q or K596Q) restored HIF2A stability in HAT1-silenced cells. The HAT1-HIF2A axis is required for hypoxia-promoted cancer stem cell maintenance. Co-immunoprecipitation (HAT1-HIF2A interaction), site-directed mutagenesis (K512Q, K596Q), ChIP (occupancy of VEGFA promoter), cancer stem cell assays, siRNA knockdown Biochimica et biophysica acta. Gene regulatory mechanisms High 36410688
2022 In plateau pika, an Epas1 mutation (24-residue insert from alternative splicing caused by a point mutation at the 5' splice site of Intron14) produces a more stable Epas1 protein. Biochemical studies showed an Epas1-Bmal1 complex with lower trans-activation activity occupies E1/E2 motifs at the Per2 promoter, disrupting the circadian clock. Mice expressing plateau pika Epas1 in the suprachiasmatic nucleus had dysregulated central clocks; pika Epas1 knock-in mice in hypoxia showed reduced heart damage. Protein stability assay, biochemical complex formation (Epas1-Bmal1), chromatin binding at Per2 promoter, transgenic/knock-in mice, circadian behavioral assay, hypoxic chamber experiments Cell reports High 35584682
2022 Deletion of a hypoxia-sensitive EPAS1 enhancer (ENH5) results in down-regulation of EPAS1 and HIF-2α target genes during acute hypoxia and blunts the transcriptional response to sustained hypoxia; ENH5 deletion in mice causes dysregulation of gene expression across multiple tissues, establishing it as a pleiotropic cis-regulatory element. CRISPR enhancer deletion in cell lines and mice, RNA-seq, hypoxia induction Science advances High 36417539
2024 BMAL1 forms a transcriptionally active heterodimer with HIF2A (a non-canonical partner) in a diurnal manner, determined by cryo-EM structure of the BMAL1-HIF2A-DNA complex revealing structural rearrangements in BMAL1. BMAL1 enhances HIF2A transcriptional activity and stabilizes HIF2A protein. The BMAL1-HIF2A complex drives rhythmic expression of amphiregulin (AREG), which regulates circadian variations in myocardial injury severity. Cryo-EM structure determination of BMAL1-HIF2A-DNA complex, co-IP, protein stability assay, ChIP, genetic knockout mice, pharmacological inhibition targeting BMAL1-HIF2A-AREG pathway Nature High 40269168
2024 EPAS1 attenuates atherosclerosis at sites of disturbed flow by maintaining endothelial cell proliferation via upregulation of fatty acid-handling molecules CD36 and LIPG, increasing fatty acid beta-oxidation. Endothelial Epas1 deletion in hypercholesterolemic mice increased lesion formation. Obesity/free fatty acids suppress EPAS1 via upregulation of PHD2. Inducible endothelial-specific Epas1 knockout mouse, adeno-associated virus-PCSK9/high-fat diet atherosclerosis model, en face immunostaining, metabolic analyses, EC flow assays Circulation research High 39234692
2024 Andean-specific EPAS1 missense variant H194R (rs570553380) is a hypomorphic allele: in vitro assays show H194R impairs binding of HIF-2α to its heterodimeric partner ARNT; CRISPR-base-edited human cells with this variant exhibit shifts in hypoxia-regulated gene expression; a knockin mouse model shows decreased hypoxia-induced pulmonary Endothelin-1 transcripts and protection against hypoxia-induced pulmonary hypertension. CRISPR base editing in human cells, RNA-seq, in vitro heterodimerization binding assay, knock-in mouse model, pulmonary hypertension phenotyping Science advances / Molecular biology and evolution High 37463421 38335297
2021 EPAS1 gain-of-function mutations (e.g., A530V) cause developmental vascular malformations: in a transgenic mouse model, retinal veins and intracranial dural veins failed to undergo normal regression at expected developmental timepoints, establishing EPAS1's role in vascular remodeling during development. Transgenic gain-of-function mouse model (Epas1-A529V), intravital 2-photon microscopy, 14T MRI, micro-CT, confocal immunofluorescence of retinal and dural vessels at developmental timepoints JCI insight High 33497361
2021 HIF2A gain-of-function mutation (G537W knock-in iPSC model) results in aberrant smooth muscle cells (SMCs) that are more contractile and stiffer, overexpressing endothelin 1 (EDN1); EDN1 inhibition and EDN1-receptor knockdown reduced HIF2A-SMC stiffness. Corresponding Hif2A GOF heterozygous mice displayed pulmonary hypertension with SMC cytoskeletal disorganization. iPSC differentiation into ECs and SMCs, atomic force microscopy (cell stiffness), EDN1 inhibition/knockdown, heterozygous GOF knock-in mouse, pulmonary arterial SMC characterization iScience High 33796838
2016 MBD3 (methylated CpG binding protein 3) binds the EPAS1 promoter in breast cancer cells and amplifies EPAS1 transcription through demethylation of CpG sites around the transcriptional start site; shRNA depletion of MBD3 decreased EPAS1 transcription and HIF2α-mediated angiogenic responses in two cancer cell lines. ChIP (MBD3 binding at EPAS1 promoter), bisulfite methylation analysis, shRNA knockdown, functional angiogenesis assay Tumour biology Medium 27465550
2015 Transcriptional regulation of HIF2A mRNA in neuroblastoma involves estrogen-related receptor alpha (ERRα): knockdown or inhibition of ERRα decreases HIF2A mRNA levels, and this regulation involves de novo transcription rather than mRNA stability. siRNA/pharmacological inhibition of ERRα, transcriptome array, actinomycin chase (de novo transcription vs. stability), qRT-PCR Biochemical and biophysical research communications Medium 25912138
2018 In retinal neuroprogenitor cells, Hif2a upregulates VEGF and erythropoietin expression and locally downregulates endostatin; Cre-lox excision of Hif2a from neuroprogenitors reduces endothelial cell proliferation at the angiogenic front, causing delayed retinal vascular development, fewer major retinal vessels, and reduced peripheral deep plexus density. Cre-lox conditional knockout of Hif2a in retinal neuroprogenitors, quantification of retinal vascular development, gene expression analysis Development (Cambridge, England) High 29615467
2024 The natural compound atractylenolide I (ATL-I) promotes autophagic degradation of EPAS1/HIF2α via upregulation of ATP6V0D2, which binds RAB7 and VPS41 to promote RAB7-HOPS interaction, facilitating SNARE complex assembly and autophagosome-lysosome fusion, thereby increasing lysosomal acidification and EPAS1 degradation. Co-immunoprecipitation (ATP6V0D2 with RAB7/VPS41), lysosomal activity assay, autophagy flux assay, Western blot, xenograft models Autophagy Medium 39477683

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes & development 1088 9000051
2010 Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders. Proceedings of the National Academy of Sciences of the United States of America 621 20534544
2004 Differentiating the functional role of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha (EPAS-1) by the use of RNA interference: erythropoietin is a HIF-2alpha target gene in Hep3B and Kelly cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 338 15240563
2002 Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer. International journal of radiation oncology, biology, physics 290 12128120
2008 A gain-of-function mutation in the HIF2A gene in familial erythrocytosis. The New England journal of medicine 267 18184961
2001 Hypoxia inducible factor (HIF-1a and HIF-2a) expression in early esophageal cancer and response to photodynamic therapy and radiotherapy. Cancer research 232 11280732
2003 The HIF family member EPAS1/HIF-2alpha is required for normal hematopoiesis in mice. Blood 165 12750163
1999 EPAS1 trans-activation during hypoxia requires p42/p44 MAPK. The Journal of biological chemistry 145 10559262
2017 Down-Regulation of EPAS1 Transcription and Genetic Adaptation of Tibetans to High-Altitude Hypoxia. Molecular biology and evolution 142 28096303
2013 Tumoral EPAS1 (HIF2A) mutations explain sporadic pheochromocytoma and paraganglioma in the absence of erythrocytosis. Human molecular genetics 141 23418310
2012 A novel EPAS1/HIF2A germline mutation in a congenital polycythemia with paraganglioma. Journal of molecular medicine (Berlin, Germany) 139 23090011
2005 The androgen receptor is significantly associated with vascular endothelial growth factor and hypoxia sensing via hypoxia-inducible factors HIF-1a, HIF-2a, and the prolyl hydroxylases in human prostate cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 135 16278385
2006 Expression of HIF-1alpha, HIF-2alpha (EPAS1), and their target genes in paraganglioma and pheochromocytoma with VHL and SDH mutations. The Journal of clinical endocrinology and metabolism 118 16954163
2013 In vivo and in vitro oncogenic effects of HIF2A mutations in pheochromocytomas and paragangliomas. Endocrine-related cancer 116 23533246
2008 Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis. Blood 106 18378852
2011 Hypoxia: adapting to high altitude by mutating EPAS-1, the gene encoding HIF-2α. High altitude medicine & biology 92 21718164
2013 Erythrocytosis and pulmonary hypertension in a mouse model of human HIF2A gain of function mutation. The Journal of biological chemistry 91 23640890
2019 EPAS1 Gain-of-Function Mutation Contributes to High-Altitude Adaptation in Tibetan Horses. Molecular biology and evolution 88 31273382
2015 PI3K-mTORC2 but not PI3K-mTORC1 regulates transcription of HIF2A/EPAS1 and vascularization in neuroblastoma. Cancer research 84 26432405
2019 HIF2A-LOX Pathway Promotes Fibrotic Tissue Remodeling in Thyroid-Associated Orbitopathy. Endocrinology 81 30388216
2021 The history and evolution of the Denisovan-EPAS1 haplotype in Tibetans. Proceedings of the National Academy of Sciences of the United States of America 74 34050022
2013 Mosaicism in HIF2A-related polycythemia-paraganglioma syndrome. The Journal of clinical endocrinology and metabolism 74 24276449
2014 Frequent EPAS1/HIF2α exons 9 and 12 mutations in non-familial pheochromocytoma. Endocrine-related cancer 67 24741025
2017 The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction. Nature communications 65 28067314
2004 EPAS1 promotes adipose differentiation in 3T3-L1 cells. The Journal of biological chemistry 65 15258146
2019 Physiological and genomic evidence that selection on the transcription factor Epas1 has altered cardiovascular function in high-altitude deer mice. PLoS genetics 59 31697676
2018 Transient HIF2A inhibition promotes satellite cell proliferation and muscle regeneration. The Journal of clinical investigation 56 29533927
2009 Mutation analysis of hypoxia-inducible factors HIF1A and HIF2A in renal cell carcinoma. Anticancer research 54 20032376
2018 Hypoxia-inducible transcription factors, HIF1A and HIF2A, increase in aging mucosal tissues. Immunology 52 29338076
2013 First report of bilateral pheochromocytoma in the clinical spectrum of HIF2A-related polycythemia-paraganglioma syndrome. The Journal of clinical endocrinology and metabolism 51 23539726
2019 LINE-1 and EPAS1 DNA methylation associations with high-altitude exposure. Epigenetics 46 30574831
1999 Cloning and expression pattern of EPAS1 in the chicken embryo. Colocalization with tyrosine hydroxylase. FEBS letters 46 10580084
1995 MOP2 (SLA2) affects the abundance of the plasma membrane H(+)-ATPase of Saccharomyces cerevisiae. The Journal of biological chemistry 46 7896828
2013 HIF2A and IGF2 expression correlates in human neuroblastoma cells and normal immature sympathetic neuroblasts. Neoplasia (New York, N.Y.) 43 23479510
2001 Regulation of vascular endothelial growth factor transcription by endothelial PAS domain protein 1 (EPAS1) and possible involvement of EPAS1 in the angiogenesis of renal cell carcinoma. Cancer 43 11301389
2005 The EPAS1 gene influences the aerobic-anaerobic contribution in elite endurance athletes. Human genetics 42 16208515
2008 Analysis of the Runx2 promoter in osseous and non-osseous cells and identification of HIF2A as a potent transcription activator. Gene 40 18442887
2025 BMAL1-HIF2A heterodimer modulates circadian variations of myocardial injury. Nature 39 40269168
2019 Convergent evolution on the hypoxia-inducible factor (HIF) pathway genes EGLN1 and EPAS1 in high-altitude ducks. Heredity 39 30631144
2017 Evidence of Early-Stage Selection on EPAS1 and GPR126 Genes in Andean High Altitude Populations. Scientific reports 36 29026132
2018 Multi-Omics Analysis Reveals a HIF Network and Hub Gene EPAS1 Associated with Lung Adenocarcinoma. EBioMedicine 35 29859855
2018 Hypoxic-stabilized EPAS1 proteins transactivate DNMT1 and cause promoter hypermethylation and transcription inhibition of EPAS1 in non-small cell lung cancer. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 35 29920222
2012 Two new mutations in the HIF2A gene associated with erythrocytosis. American journal of hematology 34 22367913
2024 Functional EPAS1/HIF2A missense variant is associated with hematocrit in Andean highlanders. Science advances 32 38335297
2019 Hypoxia-inducible factor (HIF)-prolyl hydroxylase 3 (PHD3) maintains high HIF2A mRNA levels in clear cell renal cell carcinoma. The Journal of biological chemistry 32 30617181
2016 EPAS1/HIF-2 alpha-mediated downregulation of tissue factor pathway inhibitor leads to a pro-thrombotic potential in endothelial cells. Biochimica et biophysica acta 32 26826018
2015 Differential regulation of HIF-1α and HIF-2α in neuroblastoma: Estrogen-related receptor alpha (ERRα) regulates HIF2A transcription and correlates to poor outcome. Biochemical and biophysical research communications 32 25912138
2014 Two functional loci in the promoter of EPAS1 gene involved in high-altitude adaptation of Tibetans. Scientific reports 31 25501874
2009 Erythrocytosis associated with a novel missense mutation in the HIF2A gene. Haematologica 31 20007141
2010 EPAS1 Is Required for Spermatogenesis in the Postnatal Mouse Testis. Biology of reproduction 30 20181618
2010 Combined mRNA and microRNA profiling reveals that miR-148a and miR-20b control human mesenchymal stem cell phenotype via EPAS1. Physiological genomics 30 21081659
2004 Expression of HIF-2alpha/EPAS1 in hepatocellular carcinoma. World journal of gastroenterology 30 14966910
2021 MiR-182-5p promotes the Metastasis and Epithelial-mesenchymal Transition in Non-small Cell Lung Cancer by Targeting EPAS1. Journal of Cancer 28 34729113
2013 Congenital erythrocytosis associated with gain-of-function HIF2A gene mutations and erythropoietin levels in the normal range. Haematologica 26 23716564
2019 A Transgenic Mouse Model of Pacak⁻Zhuang Syndrome with An Epas1 Gain-of-Function Mutation. Cancers 25 31091718
2022 A highland-adaptation mutation of the Epas1 protein increases its stability and disrupts the circadian clock in the plateau pika. Cell reports 24 35584682
2020 EPAS1 targeting by miR-152-3p in Paclitaxel-resistant Breast Cancer. Journal of Cancer 24 32913475
2019 Genetic changes in the EPAS1 gene between Tibetan and Han ethnic groups and adaptation to the plateau hypoxic environment. PeerJ 24 31681516
2015 EPAS1 Gene Polymorphisms Are Associated With High Altitude Polycythemia in Tibetans at the Qinghai-Tibetan Plateau. Wilderness & environmental medicine 24 25792003
2021 Developmental vascular malformations in EPAS1 gain-of-function syndrome. JCI insight 23 33497361
2016 MBD3 mediates epigenetic regulation on EPAS1 promoter in cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 23 27465550
2024 Atractylenolide I inhibits angiogenesis and reverses sunitinib resistance in clear cell renal cell carcinoma through ATP6V0D2-mediated autophagic degradation of EPAS1/HIF2α. Autophagy 22 39477683
2021 NNT-induced tumor cell "slimming" reverses the pro-carcinogenesis effect of HIF2a in tumors. Clinical and translational medicine 22 33463050
2017 Endothelial Epas1 Deficiency Is Sufficient To Promote Parietal Epithelial Cell Activation and FSGS in Experimental Hypertension. Journal of the American Society of Nephrology : JASN 22 28928136
2014 Polycythemia and paraganglioma with a novel somatic HIF2A mutation in a male. Pediatrics 22 24819565
2022 A pleiotropic hypoxia-sensitive EPAS1 enhancer is disrupted by adaptive alleles in Tibetans. Science advances 21 36417539
2015 PLGA/poloxamer nanoparticles loaded with EPAS1 siRNA for the treatment of pancreatic cancer in vitro and in vivo. International journal of molecular medicine 21 25672594
2014 EPAS1 gene variants are associated with sprint/power athletic performance in two cohorts of European athletes. BMC genomics 21 24884370
2021 HIF2A gain-of-function mutation modulates the stiffness of smooth muscle cells and compromises vascular mechanics. iScience 20 33796838
2021 Integration and Visualization of Regulatory Elements and Variations of the EPAS1 Gene in Human. Genes 20 34828399
2019 EGFR-AS1/HIF2A regulates the expression of FOXP3 to impact the cancer stemness of smoking-related non-small cell lung cancer. Therapeutic advances in medical oncology 20 31275431
2018 HIF1A is Overexpressed in Medulloblastoma and its Inhibition Reduces Proliferation and Increases EPAS1 and ATG16L1 Methylation. Current cancer drug targets 20 28302031
2017 HIF1A and EPAS1 potentiate hypoxia-induced upregulation of inhibin alpha chain expression in human term cytotrophoblasts in vitro. Molecular human reproduction 20 28115494
2015 EPAS1/HIF-2α is a driver of mammalian pexophagy. Autophagy 20 25997392
2020 EPAS1 and VEGFA gene variants are related to the symptoms of acute mountain sickness in Chinese Han population: a cross-sectional study. Military Medical Research 19 32718338
2020 PDK4 promotes tumorigenesis and cisplatin resistance in lung adenocarcinoma via transcriptional regulation of EPAS1. Cancer chemotherapy and pharmacology 19 33221963
2023 A novel HIF2A mutation causes dyslipidemia and promotes hepatic lipid accumulation. Pharmacological research 18 37453673
2020 EPAS1 regulates proliferation of erythroblasts in chronic mountain sickness. Blood cells, molecules & diseases 18 32470757
2020 EPAS1 promotes peritoneal carcinomatosis of non-small-cell lung cancer by enhancing mesothelial-mesenchymal transition. Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al] 18 32681351
2015 Somatic gain-of-function HIF2A mutations in sporadic central nervous system hemangioblastomas. Journal of neuro-oncology 18 26514359
2022 HCMV-miR-US33-5p promotes apoptosis of aortic vascular smooth muscle cells by targeting EPAS1/SLC3A2 pathway. Cellular & molecular biology letters 17 35596131
2019 Nonmosaic somatic HIF2A mutations associated with late onset polycythemia-paraganglioma syndrome: Newly recognized subclass of polycythemia-paraganglioma syndrome. Cancer 17 30644531
2018 Mutations in EPAS1 in congenital heart disease in Tibetans. Bioscience reports 17 30487161
2024 EPAS1, a hypoxia- and ferroptosis-related gene, promotes malignant behaviour of cervical cancer by ceRNA and super-enhancer. Journal of cellular and molecular medicine 16 38722283
2020 Long non-coding RNA ZFAS1 promotes the expression of EPAS1 in gastric cardia adenocarcinoma. Journal of advanced research 16 33364040
2018 Late neuroprogenitors contribute to normal retinal vascular development in a Hif2a-dependent manner. Development (Cambridge, England) 16 29615467
2023 Comprehensive in silico and functional studies for classification of EPAS1/HIF2A genetic variants identified in patients with erythrocytosis. Haematologica 15 36700397
2022 Histone acetyltransferase 1 (HAT1) acetylates hypoxia-inducible factor 2 alpha (HIF2A) to execute hypoxia response. Biochimica et biophysica acta. Gene regulatory mechanisms 15 36410688
2017 Time- and strain-specific downregulation of intestinal EPAS1 via miR-148a by Bifidobacterium bifidum. Molecular nutrition & food research 15 27883285
2017 HIF2A germline-mutation-induced polycythemia in a patient with VHL-associated renal-cell carcinoma. Cancer biology & therapy 15 29172931
2020 C-Terminal, but Not Intact, FGF23 and EPO Are Strongly Correlatively Elevated in Patients With Gain-of-Function Mutations in HIF2A: Clinical Evidence for EPO Regulating FGF23. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 14 33049075
2002 Positive expression of HIF-2alpha/EPAS1 in invasive bladder cancer. Urology 14 11992927
2024 EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites Through Endothelial Fatty Acid Uptake. Circulation research 13 39234692
2020 Molecular Deregulation of EPAS1 in the Pathogenesis of Esophageal Squamous Cell Carcinoma. Frontiers in oncology 13 33042797
2014 Analysis of candidate genes for morphine preference quantitative trait locus Mop2. Neuroscience 13 25058503
2014 Association of EPAS1 gene rs4953354 polymorphism with susceptibility to lung adenocarcinoma in female Japanese non-smokers. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 13 25436804
2023 High-Altitude Andean H194R HIF2A Allele Is a Hypomorphic Allele. Molecular biology and evolution 12 37463421
2023 Selective HIF2A Inhibitors in the Management of Clear Cell Renal Cancer and Von Hippel-Lindau-Disease-Associated Tumors. Medical sciences (Basel, Switzerland) 12 37489462
2019 Chiari Malformation Type 1 in EPAS1-Associated Syndrome. International journal of molecular sciences 12 31185588
2008 Familial erythrocytosis arising from a gain-of-function mutation in the HIF2A gene of the oxygen sensing pathway. The Ulster medical journal 12 18711622

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