HGNC Approved Gene Symbol: HBE1
Cytogenetic location: 11p15.4 Genomic coordinates (GRCh38): 11:5,268,345-5,269,945 (from NCBI)
The epsilon locus determines the epsilon, or non-alpha, chain of embryonic hemoglobin (originally known as Gower-2). No mutations affecting the epsilon chain have yet been identified. Gower-1 is a tetramer of epsilon chains. The epsilon locus may be linked to the delta-beta complex. The amino acid sequence of the epsilon chain is similar to those of the delta and beta chains. Furthermore, the homologous chain in the mouse is linked to the beta locus (Gilman and Smithies, 1968). Shen and Smithies (1982) determined the complete nucleotide sequence of the 3.4-kb stretch of DNA 5-prime to the epsilon gene where a pseudogene (psi-beta-2) was thought to reside (Fritsch et al., 1980). They concluded that no globin-related gene exists there and provided a possible explanation for the earlier contrary conclusion. By studies in transgenic mice, Raich et al. (1992) demonstrated that deletion of a 'negative element' located between -182 and -467 bp upstream of the HBE gene cap site resulted in continuation of HBE gene expression in the definitive erythroblasts of the fetal liver and in the red blood cells of adult animals. The findings provided direct in vivo evidence that cis-acting silencing elements are involved in the developmental control of the HBE gene.
Bailey et al. (1992) used the epsilon-globin gene to examine the debate as to whether all bats fall into a monophyletic order (Chiroptera) or have diphyletic origins with the megabats actually being 'flying primates.' Results of parsimony analysis supported bat monophyly.
He and Russell (2002) analyzed the anti-sickling properties of HBE both in vitro as well as in vivo in a well-established mouse model of sickle cell anemia (603903). These animals, expressing 100% of human Hb S (141900.0243), display a chronic hemolytic anemia with compensatory marrow and extramedullary erythropoiesis, abundant circulating sickled erythrocytes, and chronic tissue damage evidenced by parallel histopathologic and functional deficits. By comparison, related mice that coexpress Hb S as well as HBE exhibited normal physiologic, morphologic, histologic, and functional attributes. Subsequent in vitro analyses substantiated results from whole-animal studies, indicating that the polymerization of deoxygenated Hb S can be significantly slowed by relatively small quantities of HBE. Together, the in vivo and in vitro analyses suggested that reactivation of epsilon-globin gene expression would be therapeutically beneficial to adults with sickle phenotypes, and provide a rationale for detailed investigations into the molecular basis for its developmental silencing.
Bailey, W. J., Slightom, J. L., Goodman, M. Rejection of the 'flying primate' hypothesis by phylogenetic evidence from the epsilon-globin gene. Science 256: 86-89, 1992. Note: Erratum: Science 260: 608 only, 1993. [PubMed: 1301735] [Full Text: https://doi.org/10.1126/science.1301735]
Baralle, F. E., Shoulders, C. C., Proudfoot, N. J. The primary structure of the human epsilon-globin gene. Cell 21: 621-626, 1980. [PubMed: 6254663] [Full Text: https://doi.org/10.1016/0092-8674(80)90425-0]
Fritsch, E. F., Lawn, R. M., Maniatis, T. Molecular cloning and characterization of the human beta-like globin gene cluster. Cell 19: 959-972, 1980. [PubMed: 6155216] [Full Text: https://doi.org/10.1016/0092-8674(80)90087-2]
Gale, R. E., Clegg, J. B., Huehns, E. R. Human embryonic haemoglobins Gower 1 and Gower 2. Nature 280: 162-164, 1979. [PubMed: 95353] [Full Text: https://doi.org/10.1038/280162a0]
Gilman, J. G., Smithies, O. Fetal hemoglobin variants in mice. Science 160: 885-886, 1968. [PubMed: 5647833] [Full Text: https://doi.org/10.1126/science.160.3830.885]
He, Z., Russell, J. E. A human embryonic hemoglobin inhibits Hb S polymerization in vitro and restores a normal phenotype to mouse models of sickle cell disease. Proc. Nat. Acad. Sci. 99: 10635-10640, 2002. [PubMed: 12124399] [Full Text: https://doi.org/10.1073/pnas.162269099]
Huehns, E. R., Dance, N., Beaven, G. H., Hecht, F., Motulsky, A. G. Human embryonic hemoglobin. Nature 201: 1095-1097, 1964. [PubMed: 14152781] [Full Text: https://doi.org/10.1038/2011095a0]
Huehns, E. R., Flynn, F. V., Butler, E. A., Beaven, G. H. Two new hemoglobin variants in a very young human embryo. Nature 189: 496-497, 1961. [PubMed: 13716547] [Full Text: https://doi.org/10.1038/189496a0]
Raich, N., Papayannopoulou, T., Stamatoyannopoulos, G., Enver, T. Demonstration of a human epsilon-globin gene silencer with studies in transgenic mice. Blood 79: 861-864, 1992. [PubMed: 1737096]
Ramsay, M., Thomson, J. A., Jenkins, T. A new epsilon globin HincII variant fragment length in a South African Negroid family. J. Med. Genet. 23: 145-150, 1986. [PubMed: 3012088] [Full Text: https://doi.org/10.1136/jmg.23.2.145]
Shen, S.-H., Smithies, O. Human globin psi-beta-2 is not a globin-related sequence. Nucleic Acids Res. 10: 7809-7818, 1982. [PubMed: 6897566] [Full Text: https://doi.org/10.1093/nar/10.23.7809]