EPAS1 (HIF-2α): Hypoxia-Inducible Factor 2 Alpha Subunit
A master regulator of oxygen homeostasis, implicated in cancer, cardiovascular adaptation, and rare genetic disorders.
Gene Information Card
| Symbol | EPAS1 |
|---|---|
| Full Name | Endothelial PAS domain-containing protein 1 |
| Gene Type | Protein-coding |
| Chromosomal Location | 2p21 |
| NCBI Gene ID | 2034 ncbi.nlm.nih.gov/gene/2034 |
| Ensembl ID | ENSG00000116016 |
| UniProt ID | Q99814 |
| OMIM ID | 603349 |
| HGNC ID | 3374 |
| Aliases | HIF2A, HIF-2α, MOP2, PASD2, bHLHe73 |
Description
The EPAS1 gene encodes hypoxia-inducible factor 2 alpha (HIF-2α), a transcription factor that regulates cellular responses to low oxygen levels. It forms a heterodimer with ARNT (HIF-1β) and activates genes involved in erythropoiesis, angiogenesis, and metabolism. EPAS1 is critical for adaptation to hypoxia and is implicated in various cancers and oxygen-sensing disorders.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Erythrocytosis, familial, 4 | Gain-of-function mutations stabilize HIF-2α, leading to increased erythropoietin (EPO) production and excessive red blood cell formation. | ClinVar, OMIM |
| Paraganglioma and pheochromocytoma | Somatic or germline gain-of-function mutations in EPAS1 cause constitutive HIF-2α activation, promoting tumorigenesis in neuroendocrine tissues. | COSMIC, ClinVar, OMIM |
| Pulmonary hypertension | Overexpression of HIF-2α in pulmonary artery smooth muscle cells contributes to vascular remodeling and increased pulmonary vascular resistance. | NCBI Gene, OMIM |
| Renal cell carcinoma | EPAS1 mutations or overexpression drive tumor growth by activating hypoxia-responsive genes (e.g., VEGF, PDGF) in clear cell renal cell carcinoma. | COSMIC, NCBI Gene |
| Polycythemia | Somatic EPAS1 mutations in hematopoietic stem cells can cause polycythemia vera-like phenotypes due to enhanced EPO signaling. | ClinVar, COSMIC |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Lung | 12.4 | Medium |
| Kidney | 8.2 | Low |
| Liver | 6.1 | Low |
| Brain | 5.3 | Low |
| Heart | 4.8 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HUVEC (endothelial) | 15.2 | High expression; relevant to angiogenesis |
| HEK293 (embryonic kidney) | 9.7 | Moderate expression |
| A549 (lung carcinoma) | 7.3 | Low expression; hypoxia-inducible |
| MCF7 (breast cancer) | 5.1 | Low expression |
| K562 (leukemia) | 3.8 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| p.Pro531Ser | Missense | Rare (0.01%) | Gain-of-function; stabilizes HIF-2α, leading to erythrocytosis |
| p.Gly537Arg | Missense | Somatic in tumors | Gain-of-function; associated with paraganglioma |
| p.Arg330X | Nonsense | Very rare | Loss-of-function; may impair hypoxia response |
| c.1609G>A | Splice site | Unknown | Potential loss-of-function; affects mRNA splicing |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations in EPAS1 are rare and may impair normal hypoxia signaling, potentially leading to defective erythropoiesis or metabolic dysregulation, but clinical phenotypes are not well-defined.
Gain of Function (GOF)
Gain-of-function mutations (e.g., in the oxygen-dependent degradation domain) stabilize HIF-2α, leading to constitutive activation of target genes. This is the primary mechanism for familial erythrocytosis and paraganglioma/pheochromocytoma.
Dominant Negative (DN)
No dominant-negative mutations have been reported for EPAS1; most pathogenic variants are gain-of-function.
View complete mutation data：
Gene Ontology (GO)
| • DNA-binding transcription factor activity | • RNA polymerase II cis-regulatory region sequence-specific DNA binding |
| • protein heterodimerization activity | • signal transducer activity |
| • response to hypoxia | • positive regulation of transcription by RNA polymerase II |
| • angiogenesis | • erythrocyte differentiation |
| • regulation of reactive oxygen species metabolic process |
Pathways
• HIF-1-alpha transcription factor network
• Hypoxia response in kidney
• VEGF signaling pathway
• Erythropoietin signaling pathway
• Regulation of glycolysis
Protein Summary
HIF-2α (UniProt Q99814) is a basic helix-loop-helix (bHLH) transcription factor that dimerizes with ARNT to regulate gene expression under hypoxic conditions. It contains an oxygen-dependent degradation domain (ODDD) that is hydroxylated by prolyl hydroxylases (PHDs) under normoxia, targeting it for proteasomal degradation. Under hypoxia, HIF-2α stabilizes and translocates to the nucleus, activating genes such as EPO, VEGF, and GLUT1. It is essential for erythropoiesis, vascular development, and metabolic adaptation.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| EPAS1 Knockout HEK293 Cell Line | EDJ-KQ4540 | Human | 2034 | Details Get a Quote |
| EPAS1 Knockout HCT 116 Cell Line | EDJ-KQ27163 | Human | 2034 | Details Get a Quote |
| EPAS1 Knockout HeLa Cell Line | EDJ-KQ27164 | Human | 2034 | Details Get a Quote |
| EPAS1 Knockout A-549 Cell Line | EDJ-KQ25902 | Human | 2034 | Details Get a Quote |
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