Alternative titles; symbols
HGNC Approved Gene Symbol: GFI1
Cytogenetic location: 1p22.1 Genomic coordinates (GRCh38): 1:92,473,043-92,486,925 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p22.1 | ?Neutropenia, nonimmune chronic idiopathic, of adults | 607847 | Autosomal dominant | 3 |
| Neutropenia, severe congenital 2, autosomal dominant | 613107 | Autosomal dominant | 3 |
GFI1 is a transcriptional repressor that is transiently induced during T-cell differentiation. GFI1 plays critical roles in enhancing T helper-2 (Th2) cell expansion and in repressing induction of Th17 (see IL17A; 603149) and CD103 (ITGAE; 604682)-positive inducible regulatory T (Treg) cells (Zhu et al., 2009).
Rat T-cell lymphomas induced by Moloney murine leukemia virus (Mo-MuLV) are dependent upon interleukin-2 (IL2; 147680) for growth in cell culture. Gilks et al. (1993) grew Mo-MuLV-induced rat T-cell lymphoma lines in IL-2-free medium in order to select for IL2-independent mutants. Following selection for an IL2-independent phenotype, they cloned a full-length cDNA of the gene, symbolized Gfi1 for 'growth factor independence-1.' They speculated that the GFI1 protein may be involved in events occurring after the interaction of IL-2 with its receptor. Indeed, the GFI1 protein may regulate the expression of genes during S phase of the cell cycle in T cells.
Nolo et al. (2000) identified and characterized the Drosophila 'senseless' (sens) protein, which shares homology with the human GFI1 protein. They found that the sens gene is required for proper development of most cell types of the embryonic and adult peripheral nervous system (PNS) of Drosophila. Sens is a nuclear protein with 4 zinc fingers that is expressed and required in the sensory organ precursors (SOP) for proper proneural gene expression. It shares 87% amino acid identity with the GFI1 protein in the zinc finger domains. Ectopic expression of Sens in many ectodermal cells caused induction of PNS external sensory organ formation and was able to recreate an ectopic proneural field. Hence, sens is both necessary and sufficient for PNS development. These data indicated that proneural genes activate sens expression. Sens is then in turn required to further activate and maintain proneural gene expression. This feedback mechanism is essential for selective enhancement and maintenance of proneural gene expression in the SOPs in Drosophila.
Liu and Cowell (2000) cloned and characterized the human GFI1 promoter. They found that its nucleotide sequence is GC-rich and does not contain a typical TATA or CAAT box. Computer predictions indicated that either of 2 Sp1 sites might serve as the site for transcription initiation.
Using microarray analysis of IL4 (147780)-stimulated and unstimulated mouse Cd4 T cells, Zhu et al. (2002) identified Gfi1, a Stat6 (601512)-dependent transcriptional repressor, as a strongly induced immediate-early gene that promoted proliferation of Th2 cells during their polarization. Prolongation of Gfi1 expression by retroviral infection resulted in enhanced Il2 (147680)-induced Stat5 (STAT5A; 601511) phosphorylation and repressed p27(Kip1) (CDKN1B; 600778) expression, as well as greater proliferation. Zhu et al. (2002) concluded that GFI1, in cooperation with GATA3 (131320), plays a major role in IL4-driven CD4 T-cell proliferation.
As indicated later, Gfi1-deficient mice, produced by gene targeting, are neutropenic. Furthermore, Person et al. (2003) demonstrated that heritable GFI1 mutations cause human neutropenia. Mutant GFI1 in these cases fails to repress ELA2 (130130), encoding neutrophil elastase, mutations of which are the major cause of inherited human neutropenia syndromes. In both mice and humans with GFI1 mutations, myeloid progenitor cells fail to differentiate to mature neutrophils, causing the accumulation of monocytes and abnormal cells that blend features of monocytes and granulocytes. Only 1 cellular promoter had been known to be repressed by GFI1, that for the antiapoptotic factor BAX (600040). To identify genes regulated by GFI1 during hematopoiesis in vivo, Duan and Horwitz (2003) performed large-scale chromatin immunoprecipitation (ChIP) assays. They found that GFI1 binds to a functionally diverse set of genes acting concertedly during hematopoietic differentiation.
Hock et al. (2004) reported that GFI1 restricted proliferation of hematopoietic stem cells. After loss of GFI1, hematopoietic stem cells displayed elevated proliferation rates as assessed by 5-bromodeoxyuridine incorporation and cell cycle analysis. Gfi1 null hematopoietic stem cells were functionally compromised in competitive repopulation and serial transplantation assays and were rapidly outcompeted in the bone marrow of mouse chimeras generated with Gfi1 null embryonic stem cells. Hock et al. (2004) concluded that GFI1 is essential to restrict hematopoietic stem cell proliferation and to preserve functional integrity.
Using mouse mutants, Zeng et al. (2004) showed that Gfi1 was differentially expressed in hematopoietic stem cells and subsets of hematopoietic progenitor cells, and that loss of Gfi1 resulted in significant alteration of stem and precursor cell frequencies. Functional assays showed that Gfi1 maintained hematopoietic stem cell self-renewal, multilineage differentiation, and efficient reconstitution of hematopoiesis in transplanted hosts by restricting stem cell proliferation.
By coimmunoprecipitation assays with mouse and human cells, Saleque et al. (2007) showed that LSD1 (AOF2; 609132), COREST (RCOR; 607675), HDAC1 (601241), and HDAC2 (605164) interacted with both GFI1 and GFI1B (604383) in endogenous complexes. The N-terminal SNAG repression domain of GFI1 and GFI1B was required for their association with COREST and LSD1. Mouse Gfi1b recruited these cofactors to the majority of target gene promoters in vivo. Inhibition of Corest and Lsd1 perturbed differentiation of mouse erythroid, megakaryocytic, and granulocytic cells, as well as primary erythroid progenitors. Lsd1 depletion derepressed GFI targets in lineage-specific patterns, accompanied by enhanced histone-3 (see 602810) lys4 methylation at the respective promoters. Saleque et al. (2007) concluded that GFI complexes catalyze serial histone modification of their targets, leading to their graded silencing.
Northcott et al. (2014) described a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4 of childhood medulloblastoma (see 155255), resulting in specific and mutually exclusive activation of the growth factor-independent-1 family protooncogenes GFI1 and GFI1B. Somatic structural variants juxtapose coding sequences from either of these genes proximal to active enhancer elements, including superenhancers, instigating oncogenic activity. Northcott et al. (2014) concluded that their results, supported by evidence from mouse models, identified GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicated 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.
Bell et al. (1995) mapped the GFI1 gene to mouse chromosome 5 by linkage analysis and mapped the GFI1 gene to rat chromosome 14p22 and to human chromosome 1p22 by fluorescence in situ hybridization. The assignment to chromosome 1 was confirmed using a mapping-panel blot.
Mice lacking the transcriptional repressor oncoprotein Gfi1 are unexpectedly neutropenic (Karsunky et al., 2002; Hock et al., 2003). Person et al. (2003) screened GFI1 as a candidate for association with neutropenia in individuals without mutations in ELA2 (130130), the most common cause of autosomal dominant severe congenital neutropenia (SCN1; 202700). They found dominant-negative zinc finger mutations (N382S, 600871.0001; K403R, 600871.0002) that disabled transcriptional repressor activity. The phenotype also included immunodeficient lymphocytes and production of a circulating population of myeloid cells that appeared immature. They showed by chromatin immunoprecipitation, gel shift, reporter assays, and elevated expression of ELA2 in vivo in neutropenic individuals that GFI1 represses ELA2, thus linking these 2 genes in a common pathway involved in myeloid differentiation. The 2 amino acid substitutions found in cases of neutropenia by Person et al. (2003) involved amino acids identical in Gfi1 homologs in divergent species and also conserved in the paralog GFI1B. The N382S mutation was found in affected members of a family with SCN2 (613107), and the K403R mutation was found in an individual with nonimmune chronic idiopathic neutropenia of adults (607847).
In a 25-year-old man with cyclic neutropenia and recurrent infections that developed during childhood, Armistead et al. (2010) identified heterozygosity for the N382S mutation in the GFI1 gene that occurred in cis with the K403R mutation. The mutations were not present in either parent; the proband had no sibs. Immunologic workup showed no abnormalities in lymphocyte proliferation after T-cell receptor stimulation, but T-cell development was slightly abnormal, with increased numbers of naive T cells and fewer central memory and effector T cells compared to controls. Analysis of patient granulocytes showed abnormal intracellular location of neutrophil elastase (ELANE; 130130), which was predominantly localized outside primary granules. Armistead et al. (2010) noted that aberrant expression of ELANE may trigger the unfolded protein response and lead to apoptosis. The patient was also HLA-A2+ (see 142800) and had evidence of PRTN3 (177020)-positive cytotoxic T cells, indicating a specific autoimmunity to myeloid cells. This autoimmune feature was consistent with the cyclic nature of the phenotype in this patient.
Karsunky et al. (2002) found that Gfi1 is expressed outside the lymphoid system in granulocytes and activated macrophages, cells that mediate innate immunity (i.e., nonspecific immunity). They generated Gfi1-deficient mice (Gfi1 -/-) and showed that these animals are severely neutropenic and accumulate immature monocytic cells in blood and bone marrow. Their myeloid precursor cells were unable to differentiate into granulocytes upon stimulation with granulocyte colony-stimulating factor (138970) but could develop into mature macrophages. They found that macrophages of the Gfi1-null animals produced enhanced levels of inflammatory cytokines, such as tumor necrosis factor (191160), interleukin-10 (124092), and interleukin-1-beta (147720), when stimulated with bacterial lipopolysaccharide, and that Gfi1-null mice succumb to low doses of this endotoxin that were tolerated by wildtype mice. They concluded that Gfi1 influences the differentiation of myeloid precursors into granulocytes or monocytes and acts in limiting the inflammatory immune response.
A mutation of the POU4F3 gene (602460) underlies human autosomal dominant nonsyndromic progressive hearing loss (DFNA15; 602459). By comparing inner ear gene expression profiles of embryonic day 16.5 wildtype and Pou4f3-mutant deaf mice, Hertzano et al. (2004) identified the GFI1 gene as a target gene regulated by Pou4f3. Deficiency of Pou4f3 led to a reduction in Gfi1 expression levels, and the dynamics of Gfi1 mRNA abundance closely followed the pattern of expression for Pou4f3. Immunohistochemical and ultrastructural analyses revealed that loss of Gfi1 resulted in outer hair cell degeneration, which appeared comparable to that observed in Pou4f3 mutants. Hertzano et al. (2004) concluded that GFI1 is the first downstream target of a hair cell-specific transcription factor, and they suggested that outer hair cell degeneration in Pou4f3 mutants may be largely or entirely a result of the loss of expression of GFI1.
Zhu et al. (2006) tested the physiologic function of Gfi1 in peripheral T cells by generating conditional Gfi1-knockout mice. Deletion of Gfi impaired proliferation and increased apoptosis of Th2 cells, but not Th1 cells, in vitro and in vivo in response to Il2. Overexpression of Stat5 failed to restore normal Th2 expansion in Gfi1-deficient cells. Mutant mice infected with Schistosoma mansoni had a reduced frequency of Il4 (147780)-producing cells, whereas Th1 responses to Toxoplasma gondii were unimpaired.
Zhu et al. (2009) generated conditional knockout mice in which Gfi1 was deleted only in T cells. Chromatin immunoprecipitation, flow cytometric, and RT-PCR analyses demonstrated defects in Th2 cell expansion and enhanced Ifng (147570) production in the mutant mice. Il4-induced Gfi1 expression inhibited Il17 (603149) production, but not induction of Ror-gamma-t (602943) in cells primed with Tgfb (190180) plus Il6 (147620). Gfi1 also limited Tgfb-mediated differentiation of inducible Treg cells. In the absence of Gfi1, the percentage of natural Treg cells expressing Cd103 and Foxp3 (300292) was increased. Gfi1 expression was also downregulated by Tgfb. Zhu et al. (2009) concluded that GFI1 plays a critical role both in enhancing Th2 cell expansion and in the epigenetic regulation of Th17 and Cd103-positive inducible Treg cell differentiation.
Using N-ethyl-N-nitrosourea (ENU) mutagenesis, Ordonez-Rueda et al. (2012) generated a mouse model of neutropenia, termed Genista, that was caused by a cys318-to-tyr (C318Y) mutation in the Gfi1 gene. The mutation disrupted the core C2H2 component of the third zinc finger domain in Gfi1. Genista mice had a normal survival rate and no weight loss, and they did not require long-term antibiotic treatment like Gfi1 -/- mice. Lymphoid cell development and T- and B-cell function showed limited defects in Genista mice compared with wildtype, but bone marrow (BM) cells exhibited various defects. In particular, a small number of atypical Cd11b (ITGAM; 120980)-positive/Ly6g-intermediate neutrophils were released from BM into circulation of Genista mice, causing autoantibody-induced arthritis, immune complex-mediated lung alveolitis, and increased susceptibility to infection.
Geissler et al. (2018) found that housing conditions, specifically pathogen exposure, determined body mass and survival of Gfi1 -/- mice. Gfi1 -/- mice developed low bone mass depending on the specific pathogen load, and low bone mass was a consequence of either low or high bone-cell activity, depending on the time point of pathogen exposure. Low bone-cell activity caused osteoporosis in Gfi1 -/- mice exposed to pathogens, whereas high bone-cell activity caused osteopenia. Increased pathogen contact negatively influenced lymphocyte production in Gfi1 -/- mice. However, this defect was not rescued upon breeding under pathogen-free conditions, indicating that alterations in bone tissue in Gfi1 -/- mice were not a direct consequence of pathogen-induced differences in blood-cell production. Instead, loss of Gfi1 induced a chronic inflammatory response to pathogen exposure, thereby promoting osteoclastogenesis and reducing survival rates of mutant mice.
Muench et al. (2020) generated mouse models of human severe congenital neutropenia using patient-derived mutations in the GFI1 transcription factor. To determine the effects of these mutations, Muench et al. (2020) generated single-cell references for granulopoietic genomic states with linked epitopes, aligned mutant cells to their wildtype equivalents and identified differentially expressed genes and epigenetic loci. The authors found that GFI1-target genes are altered sequentially, as cells go through successive states of differentiation. Muench et al. (2020) concluded that their insights facilitated the genetic rescue of granulocytic specification but not postcommitment defects in innate immune effector function, and underscored the importance of evaluating the effects of mutations and therapy within each relevant cell state.
Person et al. (2003) identified a heterozygous 1412A-G transition in the GFI1 gene causing an asn382-to-ser (N382S) substitution in the fifth zinc finger in a 4-month-old boy with severe congenital neutropenia (SCN2; 613107) who had a neutrophil count of zero and marked monocytosis. The mutation segregated with his 3-year-old paternal half brother, who was identically affected, and with their father, who had recurrent pneumonia and pyogenic abscesses abating during childhood. The father's childhood blood counts were not available, but at age 27 his neutrophil count was low and monocytes high. His peripheral blood showed a population of myeloid cells that appeared immature. The myeloid, but not erythroid, colony formation potential of his cultured peripheral blood was lower than normal; nonerythroid colonies had intact differentiation to monocytes or macrophages but had an excess of myeloid precursors with no mature neutrophils. The absolute cell number of CD4 T lymphocytes was reduced. Moreover, B lymphocytes were also reduced. Peripheral blood lymphocytes from both the father and the older son showed similar trends, and both had poor uptake of 3H-thymidine after stimulation with phytohemagglutinin, alloantigen, and Candida albicans compared with normal individuals. Nonetheless, the child had adequate circulating titers to immunizations, and all immunoglobulin isotypes were present in his serum, indicating that, though reduced in number and activation potential, the T and B lymphocyte populations were functional. Person et al. (2003) demonstrated that GFI1 represses ELA2 (130130), mutant in most cases of autosomal dominant severe congenital neutropenia, linking these 2 genes in a common pathway involved in myeloid differentiation.
In a 25-year-old man with cyclic neutropenia and recurrent infections beginning in childhood, Armistead et al. (2010) identified heterozygosity for the N382S mutation. He was also heterozygous for a K403R mutation (600871.0002), which was present on the same allele. The mutations were not present in either parent; the proband had no sibs. Immunologic workup showed no abnormalities in lymphocyte proliferation after T-cell receptor stimulation, but T-cell development was slightly abnormal, with increased numbers of naive T cells and fewer central memory and effector T cells compared to controls. Analysis of patient granulocytes showed abnormal intracellular location of neutrophil elastase (ELANE; 130130), which was predominantly localized outside primary granules. Armistead et al. (2010) noted that aberrant expression of ELANE may trigger the unfolded protein response and lead to apoptosis. The patient was also HLA-A2+ (see 142800) and had evidence of PRTN3 (177020)-positive cytotoxic T cells, indicating a specific autoimmunity to myeloid cells. This autoimmune feature was consistent with the cyclic nature of the phenotype in this patient.
Nonimmune chronic idiopathic neutropenia of adults (NI-CINA; 607847) is manifested by neutropenia milder than that in severe congenital neutropenia (see SCN2, 613107), is diagnosed in adults, and also predisposes to leukemia in a subset of patients (Papadaki et al., 2002). Person et al. (2003) identified heterozygosity for a 1475A-G transition in GFI1, causing the amino acid substitution lys403-to-arg (K403R) in the sixth zinc finger. The patient had been found to be neutropenic 10 years earlier and thereafter had persistently low neutrophil count and elevated monocytes. Analysis for acquired causes had proven negative, including drug exposures and autoimmune serologies (antibodies against nuclear antigens, against double-stranded DNA, against polymorphonuclear leukocytes, and against rheumatoid factors). She was not known ever to have had a normal blood count. There was no history of infectious complications. There were no living close relatives.
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Gilks, C. B., Bear, S. E., Grimes, H. L., Tsichlis, P. N. Progression of interleukin-2 (IL-2)-dependent rat T cell lymphoma lines to IL-2-independent growth following activation of a gene (Gfi1) encoding a novel zinc finger protein. Molec. Cell Biol. 13: 1759-1768, 1993. [PubMed: 8441411] [Full Text: https://doi.org/10.1128/mcb.13.3.1759-1768.1993]
Hertzano, R., Montcouquiol, M., Rashi-Elkeles, S., Elkon, R., Yucel, R., Frankel, W. N., Rechavi, G., Moroy, T., Friedman, T. B., Kelley, M. W., Avraham, K. B. Transcription profiling of inner ears from Pou4f3(ddl/ddl) identifies Gfi1 as a target of the Pou4f3 deafness gene. Hum. Molec. Genet. 13: 2143-2153, 2004. [PubMed: 15254021] [Full Text: https://doi.org/10.1093/hmg/ddh218]
Hock, H., Hamblen, M. J., Rooke, H. M., Schindler, J. W., Saleque, S., Fujiwara, Y., Orkin, S. H. Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells. Nature 431: 1002-1007, 2004. [PubMed: 15457180] [Full Text: https://doi.org/10.1038/nature02994]
Hock, H., Hamblen, M. J., Rooke, H. M., Traver, D., Bronson, R. T., Cameron, S., Orkin, S. H. Intrinsic requirement for zinc finger transcription factor Gfi-1 in neutrophil differentiation. Immunity 18: 109-120, 2003. [PubMed: 12530980] [Full Text: https://doi.org/10.1016/s1074-7613(02)00501-0]
Karsunky, H., Zeng, H., Schmidt, T., Zevnik, B., Kluge, R., Schmid, K. W., Duhrsen, U., Moroy, T. Inflammatory reactions and severe neutropenia in mice lacking the transcriptional repressor Gfi1. Nature Genet. 30: 295-300, 2002. [PubMed: 11810106] [Full Text: https://doi.org/10.1038/ng831]
Liu, S., Cowell, J. K. Cloning and characterization of the TATA-less promoter from the human GFI1 proto-oncogene. Ann. Hum. Genet. 64: 83-86, 2000. [PubMed: 11246463] [Full Text: https://doi.org/10.1017/S0003480000007971]
Muench, D. E., Olsson, A., Ferchen, K., Pham, G., Serafin, R. A., Chutipongtanate, S., Dwivedi, P., Song, B., Hay, S., Chetal, K., Trump-Durbin, L. R., Mookerjee-Basu, J., and 10 others. Mouse models of neutropenia reveal progenitor-stage-specific defects. Nature 582: 109-114, 2020. [PubMed: 32494068] [Full Text: https://doi.org/10.1038/s41586-020-2227-7]
Nolo, R., Abbott, L. A., Bellen, H. J. Senseless, a Zn finger transcription factor, is necessary and sufficient for sensory organ development in Drosophila. Cell 102: 349-362, 2000. [PubMed: 10975525] [Full Text: https://doi.org/10.1016/s0092-8674(00)00040-4]
Northcott, P. A., Lee, C., Zichner, T., Stutz, A. M., Erkek, S., Kawauchi, D., Shih, D. J. H., Hovestadt, V., Zapatka, M., Sturm, D., Jones, D. T. W., Kool, M., and 67 others. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 511: 428-434, 2014. [PubMed: 25043047] [Full Text: https://doi.org/10.1038/nature13379]
Ordonez-Rueda, D., Jonsson, F., Mancardi, D. A., Zhao, W., Malzac, A., Liang, Y., Bertosio, E., Grenot, P., Blanquet, V., Sabrautzki, S., de Angelis, M. H., Meresse, S., Duprez, E., Bruhns, P., Malissen, B., Malissen, M. A hypomorphic mutation in the Gfi1 transcriptional repressor results in a novel form of neutropenia. Europ. J. Immun. 42: 2395-2408, 2012. [PubMed: 22684987] [Full Text: https://doi.org/10.1002/eji.201242589]
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Zhu, J., Davidson, T. S., Wei, G., Jankovic, D., Cui, K., Schones, D. E., Guo, L., Zhao, K., Shevach, E. M., Paul, W. E. Down-regulation of Gfi-1 expression by TGF-beta is important for differentiation of Th17 and CD103+ inducible regulatory T cells. J. Exp. Med. 206: 329-341, 2009. [PubMed: 19188499] [Full Text: https://doi.org/10.1084/jem.20081666]
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Zhu, J., Jankovic, D., Grinberg, A., Guo, L., Paul, W. E. Gfi-1 plays an important role in IL-2-mediated Th2 cell expansion. Proc. Nat. Acad. Sci. 103: 18214-18219, 2006. [PubMed: 17116877] [Full Text: https://doi.org/10.1073/pnas.0608981103]