Human Gene EPAS1 (uc002ruv.3) Description and Page Index
  Description: Homo sapiens endothelial PAS domain protein 1 (EPAS1), mRNA.
RefSeq Summary (NM_001430): This gene encodes a transcription factor involved in the induction of genes regulated by oxygen, which is induced as oxygen levels fall. The encoded protein contains a basic-helix-loop-helix domain protein dimerization domain as well as a domain found in proteins in signal transduction pathways which respond to oxygen levels. Mutations in this gene are associated with erythrocytosis familial type 4. [provided by RefSeq, Nov 2009]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. ##Evidence-Data-START## Transcript exon combination :: SRR1660803.156330.1, SRR1660803.67820.1 [ECO:0000332] RNAseq introns :: single sample supports all introns SAMEA1965299, SAMEA1966682 [ECO:0000348] ##Evidence-Data-END## ##RefSeq-Attributes-START## MANE Ensembl match :: ENST00000263734.5/ ENSP00000263734.3 RefSeq Select criteria :: based on conservation, expression ##RefSeq-Attributes-END##
Transcript (Including UTRs)
   Position: hg19 chr2:46,524,541-46,613,842 Size: 89,302 Total Exon Count: 16 Strand: +
Coding Region
   Position: hg19 chr2:46,525,051-46,611,799 Size: 86,749 Coding Exon Count: 16 

Page IndexSequence and LinksUniProtKB CommentsGenetic AssociationsMalaCardsCTD
Gene AllelesRNA-Seq ExpressionMicroarray ExpressionRNA StructureProtein StructureOther Species
GO AnnotationsmRNA DescriptionsPathwaysOther NamesModel InformationMethods
Data last updated: 2013-06-15

-  Sequence and Links to Tools and Databases
Genomic Sequence (chr2:46,524,541-46,613,842)mRNA (may differ from genome)Protein (870 aa)
Gene SorterGenome BrowserOther Species FASTAVisiGeneGene interactionsTable Schema
BioGPSCGAPEnsemblEntrez GeneExonPrimerGeneCards
neXtProtOMIMPubMedReactomeStanford SOURCETreefam

-  Comments and Description Text from UniProtKB
DESCRIPTION: RecName: Full=Endothelial PAS domain-containing protein 1; Short=EPAS-1; AltName: Full=Basic-helix-loop-helix-PAS protein MOP2; AltName: Full=Class E basic helix-loop-helix protein 73; Short=bHLHe73; AltName: Full=HIF-1-alpha-like factor; Short=HLF; AltName: Full=Hypoxia-inducible factor 2-alpha; Short=HIF-2-alpha; Short=HIF2-alpha; AltName: Full=Member of PAS protein 2; AltName: Full=PAS domain-containing protein 2;
FUNCTION: Transcription factor involved in the induction of oxygen regulated genes. Binds to core DNA sequence 5'-[AG]CGTG-3' within the hypoxia response element (HRE) of target gene promoters. Regulates the vascular endothelial growth factor (VEGF) expression and seems to be implicated in the development of blood vessels and the tubular system of lung. May also play a role in the formation of the endothelium that gives rise to the blood brain barrier. Potent activator of the Tie-2 tyrosine kinase expression. Activation seems to require recruitment of transcriptional coactivators such as CREBPB and probably EP300. Interaction with redox regulatory protein APEX seems to activate CTAD.
SUBUNIT: Efficient DNA binding requires dimerization with another bHLH protein. Heterodimerizes with ARNT. Interacts with CREBBP (By similarity). Interacts with EGLN1. Interacts with VHL.
INTERACTION: Q96RK4:BBS4; NbExp=2; IntAct=EBI-447470, EBI-1805814; P60228:EIF3E; NbExp=10; IntAct=EBI-447470, EBI-347740; P61244:MAX; NbExp=2; IntAct=EBI-447470, EBI-751711;
SUBCELLULAR LOCATION: Nucleus (Potential).
TISSUE SPECIFICITY: Expressed in most tissues, with highest levels in placenta, lung and heart. Selectively expressed in endothelial cells.
PTM: In normoxia, is probably hydroxylated on Pro-405 and Pro-531 by EGLN1/PHD1, EGLN2/PHD2 and/or EGLN3/PHD3. The hydroxylated prolines promote interaction with VHL, initiating rapid ubiquitination and subsequent proteasomal degradation. Under hypoxia, proline hydroxylation is impaired and ubiquitination is attenuated, resulting in stabilization (By similarity).
PTM: In normoxia, is hydroxylated on Asn-847 by HIF1AN thus probably abrogating interaction with CREBBP and EP300 and preventing transcriptional activation (By similarity).
PTM: Phosphorylated on multiple sites in the CTAD (By similarity).
PTM: The iron and 2-oxoglutarate dependent 3-hydroxylation of asparagine is (S) stereospecific within HIF CTAD domains (By similarity).
DISEASE: Defects in EPAS1 are the cause of familial erythrocytosis type 4 (ECYT4) [MIM:611783]. ECYT4 is an autosomal dominant disorder characterized by increased serum red blood cell mass, elevated hemoglobin concentration and hematocrit, and normal platelet and leukocyte counts.
SIMILARITY: Contains 1 bHLH (basic helix-loop-helix) domain.
SIMILARITY: Contains 1 PAC (PAS-associated C-terminal) domain.
SIMILARITY: Contains 2 PAS (PER-ARNT-SIM) domains.

-  Genetic Association Studies of Complex Diseases and Disorders
  Genetic Association Database (archive): EPAS1
CDC HuGE Published Literature: EPAS1
Positive Disease Associations: Body Mass Index , Body Weight , Carcinoma, Renal Cell , Coronary Disease , Cystatins , elite endurance , Hair , Waist Circumference
Related Studies:
  1. Body Mass Index
    , , . [PubMed 0]
  2. Body Weight
    , , . [PubMed 0]
  3. Body Weight
    , , . [PubMed 0]
           more ... click here to view the complete list

-  MalaCards Disease Associations
  MalaCards Gene Search: EPAS1
Diseases sorted by gene-association score: erythrocytosis, familial, 4* (1330), sporadic pheochromocytoma* (367), autosomal dominant secondary polycythemia* (350), sporadic secreting paraganglioma* (350), multiple paragangliomas associated with polycythemia* (350), hypoxia (23), retinal hemangioblastoma (18), somatostatinoma (11), erythrocytosis, familial, 2 (7), acute diarrhea (7), polycythemia (6), vein disease (6), renal cell carcinoma (5), clear cell renal cell carcinoma (4), kidney cancer (4), pheochromocytoma (2), bardet-biedl syndrome (1)
* = Manually curated disease association

-  Comparative Toxicogenomics Database (CTD)
  The following chemicals interact with this gene           more ... click here to view the complete list

+  Common Gene Haplotype Alleles
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-  RNA-Seq Expression Data from GTEx (53 Tissues, 570 Donors)
  Highest median expression: 393.34 RPKM in Lung
Total median expression: 3174.24 RPKM

View in GTEx track of Genome Browser    View at GTEx portal     View GTEx Body Map

+  Microarray Expression Data
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-  mRNA Secondary Structure of 3' and 5' UTRs
RegionFold EnergyBasesEnergy/Base
Display As
5' UTR -198.50510-0.389 Picture PostScript Text
3' UTR -608.822043-0.298 Picture PostScript Text

The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.

-  Protein Domain and Structure Information
  InterPro Domains: Graphical view of domain structure
IPR014887 - HIF-1_TAD_C
IPR021537 - HIF_alpha_subunit
IPR011598 - HLH_dom
IPR001067 - Nuc_translocat
IPR001610 - PAC
IPR000014 - PAS
IPR013767 - PAS_fold
IPR013655 - PAS_fold_3

Pfam Domains:
PF00989 - PAS fold
PF08447 - PAS fold
PF08778 - HIF-1 alpha C terminal transactivation domain
PF11413 - Hypoxia-inducible factor-1
PF13426 - PAS domain
PF14598 - PAS domain

SCOP Domains:
47459 - HLH, helix-loop-helix DNA-binding domain
55785 - PYP-like sensor domain (PAS domain)

Protein Data Bank (PDB) 3-D Structure
MuPIT help



- X-ray MuPIT
To conserve bandwidth, only the images from the first 3 structures are shown.
3F1O - X-ray MuPIT 3F1P - X-ray MuPIT 3H7W - X-ray MuPIT
3H82 - X-ray MuPIT

ModBase Predicted Comparative 3D Structure on Q99814
The pictures above may be empty if there is no ModBase structure for the protein. The ModBase structure frequently covers just a fragment of the protein. You may be asked to log onto ModBase the first time you click on the pictures. It is simplest after logging in to just click on the picture again to get to the specific info on that model.

-  Orthologous Genes in Other Species
  Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
MouseRatZebrafishD. melanogasterC. elegansS. cerevisiae
No orthologGenome BrowserNo orthologNo orthologNo orthologNo ortholog
Gene DetailsGene Details    
Gene SorterGene Sorter    
 Protein Sequence    

-  Gene Ontology (GO) Annotations with Structured Vocabulary
  Molecular Function:
GO:0000981 RNA polymerase II transcription factor activity, sequence-specific DNA binding
GO:0001077 transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding
GO:0003677 DNA binding
GO:0003700 transcription factor activity, sequence-specific DNA binding
GO:0005515 protein binding
GO:0008134 transcription factor binding
GO:0035035 histone acetyltransferase binding
GO:0046982 protein heterodimerization activity
GO:0046983 protein dimerization activity
GO:0043565 sequence-specific DNA binding

Biological Process:
GO:0001525 angiogenesis
GO:0001666 response to hypoxia
GO:0001892 embryonic placenta development
GO:0001974 blood vessel remodeling
GO:0002027 regulation of heart rate
GO:0006351 transcription, DNA-templated
GO:0006355 regulation of transcription, DNA-templated
GO:0006366 transcription from RNA polymerase II promoter
GO:0006979 response to oxidative stress
GO:0007005 mitochondrion organization
GO:0007165 signal transduction
GO:0007275 multicellular organism development
GO:0007601 visual perception
GO:0030097 hemopoiesis
GO:0030154 cell differentiation
GO:0030218 erythrocyte differentiation
GO:0030324 lung development
GO:0042415 norepinephrine metabolic process
GO:0043129 surfactant homeostasis
GO:0043619 regulation of transcription from RNA polymerase II promoter in response to oxidative stress
GO:0043687 post-translational protein modification
GO:0045944 positive regulation of transcription from RNA polymerase II promoter
GO:0048469 cell maturation
GO:0048625 myoblast fate commitment
GO:0055072 iron ion homeostasis
GO:0061418 regulation of transcription from RNA polymerase II promoter in response to hypoxia
GO:0071456 cellular response to hypoxia

Cellular Component:
GO:0005634 nucleus
GO:0005654 nucleoplasm
GO:0005667 transcription factor complex
GO:0005737 cytoplasm
GO:0005829 cytosol
GO:0016607 nuclear speck

-  Descriptions from all associated GenBank mRNAs
  BC051338 - Homo sapiens endothelial PAS domain protein 1, mRNA (cDNA clone MGC:59860 IMAGE:6305604), complete cds.
U81984 - Human endothelial PAS domain protein 1 (EPAS1) mRNA, complete cds.
U51626 - Human MOP2 mRNA, complete cds.
AB384937 - Synthetic construct DNA, clone: pF1KB4384, Homo sapiens EPAS1 gene for endothelial PAS domain-containing protein 1, complete cds, without stop codon, in Flexi system.
KY492313 - Homo sapiens HIF-2 alpha uPEP mRNA, complete cds.
JD139880 - Sequence 120904 from Patent EP1572962.
JD209071 - Sequence 190095 from Patent EP1572962.
AK123845 - Homo sapiens cDNA FLJ41851 fis, clone NT2RI3003925, highly similar to Endothelial PAS domain-containing protein 1.
JD319879 - Sequence 300903 from Patent EP1572962.
JD159159 - Sequence 140183 from Patent EP1572962.
AF052094 - Homo sapiens clone 23698 mRNA sequence.
JD227875 - Sequence 208899 from Patent EP1572962.
BC015869 - Homo sapiens endothelial PAS domain protein 1, mRNA (cDNA clone IMAGE:4701520).
KJ905739 - Synthetic construct Homo sapiens clone ccsbBroadEn_15409 EPAS1 gene, encodes complete protein.

-  Biochemical and Signaling Pathways
  KEGG - Kyoto Encyclopedia of Genes and Genomes
hsa05200 - Pathways in cancer
hsa05211 - Renal cell carcinoma

Reactome (by CSHL, EBI, and GO)

Protein Q99814 (Reactome details) participates in the following event(s):

R-HSA-1234166 Nuclear PHD1,3 hydroxylates proline residues on EPAS1 (HIF2A)
R-HSA-8856930 EPAS1 (HIF2A) and activated NR3C1 (GCR) bind PTK6 gene
R-HSA-1234179 Cytosolic PHD2,3 hydroxylates proline residues on EPAS1 (HIF2A)
R-HSA-1234171 HIF-alpha binds ARNT (HIF1-beta) forming HIF-alpha:ARNT
R-HSA-8848812 HIF1A,EPAS1 bind PTK6 gene
R-HSA-1234164 Cytosolic hydroxylation of asparagine residue in HIF alpha
R-HSA-1234183 Cytosolic VHL:EloB,C:CUL2:RBX1 binds hydroxyprolyl-HIF-alpha
R-HSA-8956103 VHL:EloB,C:NEDD8-CUL2:RBX1 complex binds hydroxyprolyl-HIF-alpha
R-HSA-1234169 Nuclear VHL:EloB,C:CUL2:RBX1 binds hydroxyprolyl-HIF-alpha
R-HSA-1234163 Cytosolic VBC complex ubiquitinylates hydroxyprolyl-HIF-alpha
R-HSA-8956106 VHL:EloB,C:NEDD8-CUL2:RBX1 complex ubiquitinylates HIF-alpha
R-HSA-1234172 Nuclear VBC complex ubiquitinylates HIF-alpha
R-HSA-1234176 Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha
R-HSA-8849473 PTK6 Expression
R-HSA-452723 Transcriptional regulation of pluripotent stem cells
R-HSA-1234158 Regulation of gene expression by Hypoxia-inducible Factor
R-HSA-1234174 Regulation of Hypoxia-inducible Factor (HIF) by oxygen
R-HSA-8848021 Signaling by PTK6
R-HSA-1266738 Developmental Biology
R-HSA-1234162 Oxygen-dependent asparagine hydroxylation of Hypoxia-inducible Factor Alpha
R-HSA-8951664 Neddylation
R-HSA-2262749 Cellular response to hypoxia
R-HSA-9006927 Signaling by Non-Receptor Tyrosine Kinases
R-HSA-597592 Post-translational protein modification
R-HSA-2262752 Cellular responses to stress
R-HSA-162582 Signal Transduction
R-HSA-392499 Metabolism of proteins
R-HSA-8953897 Cellular responses to external stimuli

-  Other Names for This Gene
  Alternate Gene Symbols: BHLHE73, EPAS1_HUMAN, HIF2A, MOP2, NM_001430, NP_001421, PASD2, Q86VA2, Q99630, Q99814
UCSC ID: uc002ruv.3
RefSeq Accession: NM_001430
Protein: Q99814 (aka EPAS1_HUMAN)
CCDS: CCDS1825.1

-  Gene Model Information
category: coding nonsense-mediated-decay: no RNA accession: NM_001430.4
exon count: 16CDS single in 3' UTR: no RNA size: 5184
ORF size: 2613CDS single in intron: no Alignment % ID: 100.00
txCdsPredict score: 5157.00frame shift in genome: no % Coverage: 99.65
has start codon: yes stop codon in genome: no # of Alignments: 1
has end codon: yes retained intron: no # AT/AC introns 0
selenocysteine: no end bleed into intron: 0# strange splices: 0
Click here for a detailed description of the fields of the table above.

-  Methods, Credits, and Use Restrictions
  Click here for details on how this gene model was made and data restrictions if any.