Alternative titles; symbols
HGNC Approved Gene Symbol: NFE2
Cytogenetic location: 12q13.13 Genomic coordinates (GRCh38): 12:54,292,111-54,301,015 (from NCBI)
The NFE2 gene encodes a hematopoietic transcription factor (summary by Jutzi et al., 2013).
Ney et al. (1993) cloned the 45-kD subunit of the human globin locus control region binding protein, NFE2, by homology to the murine gene. Immunoprecipitation experiments demonstrated in vivo association of the p45 subunit with an 18-kD protein (see MAFG, 602020, and MAFK, 600197). Because bZIP proteins bind DNA as dimers, Ney et al. (1993) considered it likely that native NFE2 is a heterodimer of 45- and 18-kD subunits.
Chan et al. (1993) likewise cloned the human homolog of mouse NFE2. Extensive survey of human tissue samples found that NFE2 expression is not limited to erythropoietic organs. Expression in the colon and testis suggested that NFE2 may participate in the regulation of genes other than globin.
Peters et al. (1993) demonstrated Nfe2 expression in the mouse small intestine and NFE2 binding activity in nuclear extracts of a human colon carcinoma cell line (Caco-2). Caco-2 cells possess properties of the small intestine, including the ability to transport iron.
By fluorescence in situ hybridization, the NFE2 gene was assigned to chromosome 12q13 (Weremowicz et al., 1993; Ney et al., 1993).
By fluorescence in situ hybridization, Chan et al. (1995) confirmed the localization to 12q13.1-q13.3 and demonstrated that 2 genes of the same family of transcription factors with many similarities of gene structure, NFE2L1 (163260) and NFE2L2 (600492), are each located on other chromosomes. The 3 genes probably were derived from a single ancestor by chromosomal duplication inasmuch as other genes that also map to the 3 chromosomal regions are related to one another.
Jutzi et al. (2013) identified 7 different somatic insertion or deletion mutations in the NFE2 gene in 8 patients with myeloproliferative disorders, including 3 with polycythemia vera (PV; 263300) and 5 with myelofibrosis (254450), either primary or secondary. In vitro studies showed that the mutant truncated NFE2 proteins were unable to bind DNA and had lost reporter gene activity. However, coexpression of mutant NFE2 constructs with wildtype NFE2 resulted in significantly enhanced transcriptional activity. Analysis of patient cells showed low levels of the mutant truncated protein, but increased levels of the wildtype NFE2 protein compared to control cells, likely due to both increased mRNA and increased stability of the wildtype protein. All 7 patients tested also carried a JAK2 V617F mutation (147796.0001). Hematopoietic cell colonies grown from 3 patients showed that the NFE2 mutation was acquired subsequent to the JAK2 mutation, and further cellular studies indicated that an NFE2 mutation conferred a proliferative advantage of cells compared to cells carrying only the JAK2 mutation. Cells carrying mutant NFE2 displayed an increase in the proportion of cells in the S phase, consistent with enhanced cell division and proliferation, and this was associated with higher levels of cell cycle regulators. These findings were replicated in mice carrying NFE2 mutations, who developed thrombocytosis, erythrocytosis, and neutrophilia.
Peters et al. (1993) mapped the Nfe2 gene to mouse chromosome 15 in a region containing the microcytic anemia (mk) gene. Homozygous mk mice were shown by Bannerman et al. (1972) to have defective intestinal iron transport and severe anemia. Peters et al. (1993) identified what they thought was a mutation in the Nfe2 gene in mk mice (V173A), but later confirmed the change to be a polymorphism.
The mechanisms regulating the formation of blood platelets within megakaryocytes are not fully understood. Shivdasani et al. (1995) generated mice lacking the hematopoietic subunit (p45) of the heterodimeric erythroid transcription factor Nfe2. Unexpectedly, homozygous Nfe2-deficient mice lacked circulating platelets and died of hemorrhage; their megakaryocytes showed no cytoplasmic platelet formation. Though platelets were absent, serum levels of the growth factor thrombopoietin/Mgdf (600044) were not elevated above those of controls. Nevertheless, the homozygous Nfe2 deficient megakaryocytes proliferated in vivo in response to thrombopoietin administration. Thus, the authors concluded that, as an essential factor for megakaryocyte maturation and platelet production, NFE2 must regulate critical target genes independent of the action of thrombopoietin. In contrast to the dramatic absence of circulating platelets in homozygous mutant mice, the effect of loss of Nfe2 on the erythroid lineage was surprisingly mild (Shivdasani and Orkin, 1995). Although neonates exhibited severe anemia and dysmorphic red cell changes, probably compounded by concomitant bleeding, surviving adults exhibited only mild changes consistent with a small decrease in the hemoglobin content per cell. p45 Nfe2-null mice responded to anemia with compensatory reticulocytosis and splenomegaly. Globin chain synthesis was balanced, and switching from fetal to adult globins progressed normally. Although these findings were consistent with the substitution of NFE2 function in vivo by one or more compensating proteins, gel shift assays using nuclear extracts from p45 Nfe2-null mice failed to reveal novel complexes formed on an Nfe2 binding site. Thus, the authors concluded that regulation of globin gene transcription through NFE2 binding sites in vivo is more complex than had previously been appreciated.
Kaufmann et al. (2012) found that mice with overexpression of the Nfe2 gene in hematopoietic cells developed features of myeloproliferative disorders, including thrombocytosis, leukocytosis, Epo-independent colony formation, characteristic bone marrow histology, expansion of stem and progenitor compartments, and spontaneous transformation to acute myeloid leukemia. This phenotype was transplantable to secondary recipient mice. Cells from Nfe2 transgenic mice showed hypoacetylation of histone H3 (602810). Treatment of mice with a histone deacetylase inhibitor (HDAC-I) restored physiologic levels of histone H3 acetylation, decreased Nfe2 expression, and normalized platelet numbers. Similarly, patients with myeloproliferative disorders treated with an HDAC-I showed a decrease in NFE2 expression. These data established a role for aberrant NFE2 expression in the pathophysiology of myeloproliferative disorders.
Bannerman, R. M., Edwards, J. A., Kreimer-Birnbaum, M., McFarland, E., Russell, E. S. Hereditary microcytic anaemia in the mouse; studies in iron distribution and metabolism. Brit. J. Haemat. 23: 235-245, 1972. [PubMed: 5070129] [Full Text: https://doi.org/10.1111/j.1365-2141.1972.tb03476.x]
Chan, J. Y., Cheung, M.-C., Moi, P., Chan, K., Kan, Y. W. Chromosomal localization of the human NF-E2 family of bZIP transcription factors by fluorescence in situ hybridization. Hum. Genet. 95: 265-269, 1995. [PubMed: 7868116] [Full Text: https://doi.org/10.1007/BF00225191]
Chan, J. Y., Han, X.-L., Kan, Y. W. Isolation of cDNA encoding the human NF-E2 protein. Proc. Nat. Acad. Sci. 90: 11366-11370, 1993. [PubMed: 8248255] [Full Text: https://doi.org/10.1073/pnas.90.23.11366]
Jutzi, J. S., Bogeska, R., Nikoloski, G., Schmid, C. A., Seeger, T. S., Stegelmann, F., Schwemmers, S., Grunder, A., Peeken, J. C., Gothwal, M., Wehrle, J., Aumann, K., Hamdi, K., Dierks, C., Wang, W., Dohner, K., Jansen, J. H., Pahl, H. L. MPN patients harbor recurrent truncating mutations in transcription factor NF-E2. J. Exp. Med. 210: 1003-1019, 2013. [PubMed: 23589569] [Full Text: https://doi.org/10.1084/jem.20120521]
Kaufmann, K. B., Grunder, A., Hadlich, T., Wehrle, J., Gothwal, M., Bogeska, R., Seeger, T. S., Kayser, S., Pham, K.-B., Jutzi, J. S., Ganzenmuller, L., Steinemann, D., and 11 others. A novel murine model of myeloproliferative disorders generated by overexpression of the transcription factor NF-E2. J. Exp. Med. 209: 35-50, 2012. [PubMed: 22231305] [Full Text: https://doi.org/10.1084/jem.20110540]
Ney, P. A., Andrews, N. C., Jane, S. M., Safer, B., Purucker, M. E., Weremowicz, S., Morton, C. C., Goff, S. C., Orkin, S. H., Nienhuis, A. W. Purification of the human NF-E2 complex: cDNA cloning of the hematopoietic cell-specific subunit and evidence for an associated partner. Molec. Cell. Biol. 13: 5604-5612, 1993. [PubMed: 8355703] [Full Text: https://doi.org/10.1128/mcb.13.9.5604-5612.1993]
Peters, L. L., Andrews, N. C., Eicher, E. M., Davidson, M. B., Orkin, S. H., Lux, S. E. Mouse microcytic anaemia caused by a defect in the gene encoding the globin enhancer-binding protein NF-E2. Nature 362: 768-770, 1993. Note: Erratum: Nature 371: 358 only, 1994. [PubMed: 8469289] [Full Text: https://doi.org/10.1038/362768a0]
Peters, L. L., Bishop, T. R., Andrews, N. C. Globin-enhancer binding factor NF-E2 is implicated in the regulation of heme biosynthesis and iron uptake in mk/mk mice. (Abstract) Blood 82 (suppl. 1): 179a, 1993.
Shivdasani, R. A., Orkin, S. H. Erythropoiesis and globin gene expression in mice lacking the transcription factor NF-E2. Proc. Nat. Acad. Sci. 92: 8690-8694, 1995. [PubMed: 7567998] [Full Text: https://doi.org/10.1073/pnas.92.19.8690]
Shivdasani, R. A., Rosenblatt, M. F., Zucker-Franklin, D., Jackson, C. W., Hunt, P., Saris, C. J. M., Orkin, S. H. Transcription factor NF-E2 is required for platelet formation independent of the actions of thrombopoietin/MGDF in megakaryocyte development. Cell 81: 695-704, 1995. [PubMed: 7774011] [Full Text: https://doi.org/10.1016/0092-8674(95)90531-6]
Weremowicz, S., Andrews, N. C., Orkin, S. H., Morton, C. C. Mapping the p45 subunit of human NFE2 to 12q13. (Abstract) Human Genome Mapping Workshop 93, Kobe, Japan 1993. P. 25.