Open Access Articles- Top Results for EPAS1


SymbolsEPAS1 ; ECYT4; HIF2A; HLF; MOP2; PASD2; bHLHe73
External IDsOMIM603349 MGI109169 HomoloGene1095 ChEMBL: 1744522 GeneCards: EPAS1 Gene
RNA expression pattern
File:PBB GE EPAS1 200878 at tn.png
File:PBB GE EPAS1 200879 s at tn.png
More reference expression data
RefSeq (mRNA)NM_001430NM_010137
RefSeq (protein)NP_001421NP_034267
Location (UCSC)Chr 2:
46.52 – 46.61 Mb
Chr 17:
86.75 – 86.83 Mb
PubMed search[1][2]

Endothelial PAS domain-containing protein 1 (EPAS1, also known as Hypoxia-inducible factor-2alpha (HIF-2alpha)) is a protein that in humans is encoded by the EPAS1 gene. It is a type of hypoxia-inducible factors, a group of transcription factors involved in body response to oxygen level.[1][2][3][4] The gene is active under low oxygen condition called hypoxia. It is also important in the development of heart, and maintaining catecholamine balance required for protection of the heart. Mutation often leads to neuroendocrine tumors.

However, a special version (allele) of EPAS1 produces EPAS1 which is responsible for high-altitude adaptation in humans.[5][6] It is known that the variant gene confers increased athletic performance in some people, and hence, is dubbed the "super athlete gene".[7]


The EPAS1 gene encodes a half of a transcription factor involved in the induction of genes regulated by oxygen, which is induced as oxygen levels fall (hypoxia). 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. EPAS 1 is involved in the development of the embryonic heart and is expressed in the endothelial cells that line the walls of the blood vessels in the umbilical cord. It is essential in maintaining catecholamine homeostasis and protection against heart failure during early embryonic development.[4]

Catecholamines include epinephrine and norepinephrine. It is important for the production of catecholamines to remain in homeostatic conditions so that both the delicate fetal heart and the adult heart do not overexert themselves and induce heart failure. Catecholamine production in the embryo is related to control of cardiac output by increasing the fetal heart rate.[8]


Tibetans carry a high proportion of an allele that improves oxygen transport. The beneficial allele is also found in the extinct Denisovan genome, suggesting that it arose in them and entered the modern human population by hybridization.[9]

Clinical significance

Mutations in EPAS1 gene are related to early onset of neuroendocrine tumors such as paragangliomas, somatostatinomas and/or pheochromocytomas. The mutations are commonly somatic missense mutations that locate in the primary hydroxylation site of HIF-2α, which disrupt the protein hydroxylation/degradation mechanism, and leads to protein stabilization and pseudohypoxic signaling. In addition, these neuroendocrine tumors release erythropoietin (EPO) into circulating blood, and lead to polycythemia.[10][11]

Mutations in this gene are associated with erythrocytosis familial type 4,[4] pulmonary hypertension and chronic mountain sickness.[12] There is also evidence that certain variants of this gene provide protection for people living at high altitude such as in Tibet.[5][6][13] The effect is most profound among the Tibetans living in the Himalayas at an altitude of about 4,000 metres above sea level, the environment of which is intolerable to other human populations due to 40% less of atmospheric oxygen. The Tibetans suffer no health problems associated with altitude sickness, but instead produce low level of blood pigment (haemoglobin) sufficient for less oxygen, more elaborate blood vessels,[14] and exhibit extraordinary high birth weight.[15]

EPAS1 is useful in high altitudes as a short term adaptive response. However, EPAS1 can also cause excessive production of red blood cells leading to chronic mountain sickness that can lead to death and inhibited reproductive abilities. Some mutations that increase its expression are associated with increased hypertension and stroke at low altitude, with symptoms similar to mountain sickness. People permanently living at high altitudes might experience selection of EPAS1 to reduce the fitness consequences of excessive red blood cell production.[13]


EPAS1 has been shown to interact with Aryl hydrocarbon receptor nuclear translocator[1] and ARNTL.[16]


  1. ^ a b Tian H, McKnight SL, Russell DW (1997). "Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells". Genes & Development 11 (1): 72–82. PMID 9000051. doi:10.1101/gad.11.1.72. 
  2. ^ Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray-Grant M et al. (May 1997). "Characterization of a subset of the basic helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway". J Biol Chem 272 (13): 8581–93. PMID 9079689. doi:10.1074/jbc.272.13.8581. 
  3. ^ Percy MJ, Beer PA, Campbell G, Dekker AW, Green AR, Oscier D et al. (2008). "Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis". Blood 111 (11): 5400–2. PMC 2396730. PMID 18378852. doi:10.1182/blood-2008-02-137703. 
  4. ^ a b c "Entrez Gene: EPAS1 endothelial PAS domain protein 1". 
  5. ^ a b Yi X, Liang Y, Huerta-Sanchez E, Jin X, Cuo ZX, Pool JE et al. (2010). "Sequencing of 50 Human Exomes Reveals Adaptation to High Altitude". Science 329 (5987): 75–78. PMID 20595611. doi:10.1126/science.1190371. 
  6. ^ a b Hanaoka M, Droma Y, Basnyat B, Ito M, Kobayashi N, Katsuyama Y et al. (2012). "Genetic Variants in EPAS1 Contribute to Adaptation to High-Altitude Hypoxia in Sherpas". PLoS ONE 7 (12): e50566. PMC 3515610. PMID 23227185. doi:10.1371/journal.pone.0050566. 
  7. ^ Algar, Jim (1 July 2014). "Tibetan 'super athlete' gene courtesy of an extinct human species". Tech Times. Retrieved 22 July 2014. 
  8. ^ Tian H, Hammer RE, Matsumoto AM, Russell DW, McKnight SL (November 1998). "The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development". Genes Dev. 12 (21): 3320–4. PMC 317225. PMID 9808618. doi:10.1101/gad.12.21.3320. 
  9. ^ Jeong C, Alkorta-Aranburu G, Basnyat B, Neupane M, Witonsky DB, Pritchard JK et al. (2014-02-10). "Admixture facilitates genetic adaptations to high altitude in Tibet". Nature Communications 5: 3281. PMID 24513612. doi:10.1038/ncomms4281. 
  10. ^ Zhuang Z, Yang C, Lorenzo F, Merino M, Fojo T, Kebebew E et al. (September 2012). "Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia". N. Engl. J. Med. 367 (10): 922–30. PMC 3432945. PMID 22931260. doi:10.1056/NEJMoa1205119. 
  11. ^ Yang C, Sun MG, Matro J, Huynh TT, Rahimpour S, Prchal JT et al. (March 2013). "Novel HIF2A mutations disrupt oxygen sensing, leading to polycythemia, paragangliomas, and somatostatinomas". Blood 121 (13): 2563–6. PMC 3612863. PMID 23361906. doi:10.1182/blood-2012-10-460972. 
  12. ^ Gale DP, Harten SK, Reid CD, Tuddenham EG, Maxwell PH (August 2008). "Autosomal dominant erythrocytosis and pulmonary arterial hypertension associated with an activating HIF2 alpha mutation". Blood 112 (3): 919–21. PMID 18650473. doi:10.1182/blood-2008-04-153718. 
  13. ^ a b Beall CM, Cavalleri GL, Deng L, Elston RC, Gao Y, Knight J et al. (June 2010). "Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders". Proc. Natl. Acad. Sci. U.S.A. 107 (25): 11459–64. PMC 2895075. PMID 20534544. doi:10.1073/pnas.1002443107. 
  14. ^ Beall CM (2006). "Andean, Tibetan, and Ethiopian patterns of adaptation to high-altitude hypoxia". Integrative and Comparative Biology 46 (1): 18–24. PMID 21672719. doi:10.1093/icb/icj004. 
  15. ^ Beall CM, Song K, Elston RC, Goldstein MC (2004). "Higher offspring survival among Tibetan women with high oxygen saturation genotypes residing at 4,000 m". Proceedings of the National Academy of Sciences 101 (39): 14300–14304. PMID 15353580. doi:10.1073/pnas.0405949101. 
  16. ^ Hogenesch JB, Gu YZ, Jain S, Bradfield CA (May 1998). "The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors". Proc. Natl. Acad. Sci. U.S.A. 95 (10): 5474–9. PMC 20401. PMID 9576906. doi:10.1073/pnas.95.10.5474. 

Further reading


External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.