Affinage

GFI1

Zinc finger protein Gfi-1 · UniProt Q99684

Length
422 aa
Mass
45.3 kDa
Annotated
2026-04-28
100 papers in source corpus 48 papers cited in narrative 48 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GFI1 is a SNAG-domain zinc finger transcriptional repressor that governs hematopoietic stem cell quiescence, neutrophil and lymphocyte differentiation, intestinal secretory lineage specification, and inner ear hair cell survival. It binds a consensus TAAATCAC(A/T)GCA sequence through zinc fingers 3–5 in the major groove and silences target genes—including ELA2, p21, p15, Bax, Id2, CXCR4, IL-17, and CD39/CD73—by recruiting an LSD1/CoREST/HDAC1-2 corepressor complex via its SNAG domain (whose activity requires SMYD2-mediated K8 methylation) and independently recruiting G9a/HDAC1 to install repressive H3K9me2 marks (PMID:8754800, PMID:17707228, PMID:27480105, PMID:16287849). Beyond canonical DNA-binding-dependent repression, GFI1 antagonizes PU.1 and NF-κB p65 through direct protein–protein interactions, cooperates with Miz-1 to repress p21 and p15 promoters independently of its own DNA-binding sites, modulates CD45 alternative splicing via interaction with U2AF26, and facilitates PRMT1-mediated arginine methylation of DNA repair factors MRE11 and 53BP1 (PMID:17197705, PMID:20547752, PMID:19164764, PMID:16819553, PMID:29651020). GFI1 protein stability is controlled by GSK3β-mediated phosphorylation that triggers SCF-FBXW7 ubiquitin-dependent degradation and is counterbalanced by the ubiquitin ligase Triad1, while dominant-negative zinc finger mutations in GFI1 cause severe congenital neutropenia in humans (PMID:31289136, PMID:17646546, PMID:12778173).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1993 High

    GFI1 was identified as a novel zinc finger gene whose retroviral activation conferred IL-2-independent growth on T-cell lymphoma lines, establishing it as a candidate proto-oncogene in lymphoid cells.

    Evidence Retroviral provirus integration cloning and cDNA transduction rescue in IL-2-dependent T cells

    PMID:8441411

    Open questions at the time
    • Mechanism of growth factor independence unknown
    • No target genes identified
    • No normal physiological role established
  2. 1996 High

    Biochemical dissection showed GFI1 is a sequence-specific DNA-binding transcriptional repressor that requires its N-terminal SNAG domain for repressor activity, establishing the two-domain architecture (SNAG + zinc fingers) as the functional framework.

    Evidence Random oligonucleotide selection, EMSA, DNase I footprinting, SNAG-domain mutagenesis, reporter assays, IL-2 withdrawal growth assays

    PMID:8754800 PMID:8887656 PMID:8962093

    Open questions at the time
    • Cofactors mediating SNAG-dependent repression unknown
    • Full spectrum of in vivo target genes unknown
  3. 2002 High

    Gfi1 knockout mice revealed that GFI1 is essential for granulocyte differentiation and restraint of macrophage inflammatory cytokine production, establishing its non-redundant role in myeloid lineage commitment.

    Evidence Gene-targeted Gfi1−/− mice, bone marrow differentiation with G-CSF, cytokine quantification

    PMID:11810106 PMID:12530980

    Open questions at the time
    • Downstream transcriptional program not fully mapped
    • Whether HSC defects also contribute to neutropenia not yet addressed
  4. 2003 High

    Identification of ELA2 as a direct GFI1 target gene linked the repressor mechanism to human severe congenital neutropenia (SCN), as dominant-negative GFI1 zinc finger mutations caused neutropenia with derepressed ELA2.

    Evidence ChIP, EMSA, reporter assays, patient genotyping and ELA2 RT-PCR

    PMID:12778173

    Open questions at the time
    • Full penetrance and genotype-phenotype relationships across GFI1 mutations not established
    • How dominant-negative alleles disrupt wild-type GFI1 function mechanistically unclear
  5. 2003 Medium

    GFI1 was shown to associate with HDAC1/2/3 and the corepressor ETO in nuclear matrix–associated punctate structures, and its repression was TSA-sensitive, providing the first evidence that HDAC recruitment mediates GFI1-dependent silencing.

    Evidence Co-immunoprecipitation, nuclear matrix fractionation, co-localization imaging, TSA treatment

    PMID:12721361 PMID:12874834

    Open questions at the time
    • Direct versus indirect HDAC recruitment not distinguished
    • Relative contribution of individual HDACs unclear
  6. 2004 High

    GFI1 was found to restrict HSC proliferation and maintain long-term self-renewal capacity, and to autoregulate its own promoter, expanding its role from lineage commitment to stem cell quiescence and homeostatic feedback.

    Evidence BrdU incorporation, competitive repopulation, serial transplantation in Gfi1−/− mice; ChIP at Gfi1 promoter in thymocytes, reporter assays, GFP knock-in mice

    PMID:15131254 PMID:15252036 PMID:15385956 PMID:15457180

    Open questions at the time
    • Target genes responsible for HSC quiescence not identified
    • Whether GFI1 acts through cell-cycle inhibitor repression or other mechanism in HSCs unclear
  7. 2005 High

    Discovery that GFI1 recruits histone methyltransferase G9a and HDAC1 to deposit repressive H3K9me2 at the p21 promoter established a direct chromatin-modifying mechanism beyond simple HDAC-dependent deacetylation, and parallel work showed GFI1 specifies intestinal secretory lineages downstream of Atoh1.

    Evidence Co-IP, ChIP for G9a/HDAC1/H3K9me2 occupancy, siRNA knockdown; Gfi1−/− intestinal histology with Math1 epistasis

    PMID:16230531 PMID:16287849

    Open questions at the time
    • How G9a and LSD1/CoREST pathways are coordinated or context-selected at different loci unknown
    • Direct intestinal target genes not yet identified by ChIP
  8. 2006 High

    Two non-canonical GFI1 functions were uncovered: physical antagonism of PU.1 to block macrophage fate, and interaction with splice factor U2AF26 to regulate CD45 isoform usage, showing GFI1 acts beyond simple DNA-binding-dependent repression.

    Evidence Co-IP of GFI1–PU.1 and GFI1–U2AF26, reporter assays, Gfi1/PU.1 compound mutant mice, T-cell CD45 splicing assays

    PMID:16819553 PMID:17197705

    Open questions at the time
    • Structural basis of GFI1–PU.1 interaction unknown
    • Whether CD45 splicing regulation is widespread or T-cell-specific not established
  9. 2007 High

    Purification of the GFI1/GFI1B SNAG-domain complex identified LSD1/CoREST/HDAC1-2 as the major corepressor module, and Triad1 was found to stabilize GFI1 by inhibiting its ubiquitination, providing the first comprehensive picture of SNAG-mediated cofactor assembly and GFI1 turnover regulation.

    Evidence Affinity purification/mass spectrometry of GFI1B complex, ChIP for LSD1/CoREST/H3K4me, siRNA knockdown; Triad1 co-IP, ubiquitination assays, half-life measurement

    PMID:17646546 PMID:17707228

    Open questions at the time
    • How Triad1 inhibits (rather than promotes) GFI1 ubiquitination mechanistically unclear
    • Identity of the E3 ligase that degrades GFI1 not yet known
  10. 2009 High

    GFI1 was shown to repress p21 and p15 in a DNA-binding-independent manner through Miz-1 tethering, and to silence IL-17 and CD103 loci via LSD1-dependent H3K4 demethylation in Th17 cells regulated by TGF-β, revealing two distinct modes of target gene access.

    Evidence Co-IP of GFI1–Miz-1, ChIP at CDKN1A/CDKN2B promoters, ChIP for GFI1-LSD1 at Il17a/f and Cd103, H3K4me3 ChIP in Gfi1−/− cells, conditional KO with EAE model

    PMID:19164764 PMID:19188499 PMID:20190815

    Open questions at the time
    • Genome-wide prevalence of Miz-1-tethered versus direct DNA-binding repression not quantified
    • Structural basis of GFI1–Miz-1 interaction unknown
  11. 2010 High

    Multiple studies filled in the GFI1 target gene repertoire—Id2 repression underlies B-cell defects, CXCR4 repression links GFI1 to G-CSF-induced mobilization, RasGRP1 activation connects GFI1 to Erk signaling, and p65 antagonism explains macrophage hyperinflammation—while NMR resolved the ZF3-5/DNA structure at atomic resolution.

    Evidence ChIP, reporter assays, genetic epistasis in Gfi1−/− mice, solution NMR of ZF3-5/DNA complex, co-IP of GFI1–p65

    PMID:17596540 PMID:20153336 PMID:20203268 PMID:20453161 PMID:20547752

    Open questions at the time
    • Genome-wide ChIP-seq map in primary hematopoietic cells still lacking
    • How GFI1 simultaneously activates some targets (RasGRP1, Il1rl1) while repressing others mechanistically unexplained
  12. 2016 High

    SMYD2 was identified as the methyltransferase that methylates GFI1-K8 in the SNAG domain, a modification required for LSD1 recruitment and transcriptional repression, providing the upstream regulatory step for corepressor assembly.

    Evidence In vitro methylation assay, K8 mutagenesis, ChIP for H3K4me2, zebrafish rescue, leukemia cell growth assays

    PMID:27480105

    Open questions at the time
    • Whether SMYD2-K8me is dynamically regulated during differentiation unknown
    • Demethylase that reverses K8 methylation not identified
  13. 2018 High

    Two advances clarified GFI1's non-transcriptional functions and pharmacological vulnerability: GFI1 enables PRMT1-mediated arginine methylation of DNA repair factors MRE11 and 53BP1, and LSD1 inhibitors act therapeutically in AML by physically disrupting the LSD1–GFI1 SNAG interaction at enhancers rather than by blocking LSD1 catalytic activity.

    Evidence Co-IP of GFI1–PRMT1–MRE11–53BP1, in vitro methylation, Gfi1−/− irradiation sensitivity; ChIP-seq for LSD1/GFI1/RCOR1/H3K27ac with LSD1 inhibitors, demethylase-dead mutant rescue in AML cells

    PMID:29590629 PMID:29651020

    Open questions at the time
    • How GFI1 scaffolds PRMT1 substrate recognition structurally unresolved
    • Whether LSD1 inhibitor–GFI1 disruption applies beyond AML not tested
  14. 2019 High

    The phosphodegron controlling GFI1 stability was mapped: GSK3β phosphorylates S94/S98, creating an FBXW7 recognition motif for SCF-mediated ubiquitination; separately, LSD1 recruitment by GFI1 was shown to be essential for GFI1-driven medulloblastoma tumorigenesis.

    Evidence Phosphorylation/ubiquitination assays with S94A/S98A mutagenesis, GSK3β inhibitor treatment, tumor growth assays; co-IP and Lsd1 conditional KO in GFI1-driven medulloblastoma model

    PMID:30659187 PMID:31289136

    Open questions at the time
    • Signaling pathways that regulate GSK3β-GFI1 axis in normal hematopoiesis not established
    • Whether Triad1 and FBXW7 act on overlapping or distinct GFI1 pools unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • A comprehensive genome-wide map of GFI1 binding and chromatin state transitions during each hematopoietic differentiation step is still lacking, and how GFI1 switches between repressor and apparent activator modes (e.g., Il1rl1, RasGRP1) remains mechanistically unresolved.
  • No genome-wide GFI1 occupancy time-course across hematopoietic differentiation stages
  • Mechanism by which GFI1 activates select loci despite being a canonical repressor unknown
  • Structural basis of the SNAG-K8me–LSD1 interface not determined at atomic resolution

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 9 GO:0003677 DNA binding 4 GO:0098772 molecular function regulator activity 3 GO:0042393 histone binding 2
Localization
GO:0005634 nucleus 4
Pathway
R-HSA-74160 Gene expression (Transcription) 7 R-HSA-168256 Immune System 6 R-HSA-1266738 Developmental Biology 5 R-HSA-1640170 Cell Cycle 4 R-HSA-1643685 Disease 4 R-HSA-4839726 Chromatin organization 4 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 1
Partners
FBXW7G9AHDAC1LSD1PRMT1PU.1RCOR1SMYD2
Complex memberships
GFI1–G9a–HDAC1 complexGFI1–Miz-1–c-Myc complexLSD1/CoREST/HDAC1/2 corepressor complex

Evidence

Reading pass · 48 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 GFI1 encodes a zinc finger protein whose proviral activation in IL-2-dependent T-cell lymphoma lines promotes IL-2-independent growth, identifying it as an oncogene activated by promoter insertion. Retroviral provirus integration cloning, retroviral transduction of Gfi1 cDNA into IL-2-dependent cells Molecular and cellular biology High 8441411
1996 GFI1 is a 55-kDa nuclear protein that binds DNA in a sequence-specific manner (consensus TAAATCAC(A/T)GCA) through zinc fingers 3, 4, and 5, and functions as a transcriptional repressor. Random oligonucleotide selection with GST-GFI1 fusion protein, EMSA, DNase I footprinting, methylation interference, deletion mutagenesis, reporter assays in NIH 3T3 cells Molecular and cellular biology High 8754800
1996 GFI1 contains an N-terminal 20-amino-acid SNAG domain that is necessary for transcriptional repressor activity; a P2A point mutation in the SNAG domain abolishes both repression and the ability to rescue G1 arrest induced by IL-2 withdrawal. Deletion and point mutagenesis of SNAG domain, reporter assays, IL-2 withdrawal growth assays Molecular and cellular biology High 8887656
1996 GFI1 directly represses the pro-apoptotic Bax gene through Gfi1-binding sites in the Bax promoter, inhibiting T-cell death; it also represses Bak. Reporter assays with Bax promoter constructs, IL-2 withdrawal apoptosis assays, Western blot for Bax/Bak protein levels in transgenic thymocytes Proceedings of the National Academy of Sciences of the United States of America High 8962093
2000 GFI1 physically interacts with the STAT3 inhibitor PIAS3, co-localizes with PIAS3 in nuclear dot structures, and overcomes PIAS3-mediated inhibition to enhance STAT3-dependent transcription. Yeast two-hybrid screen, co-precipitation from eukaryotic cells, co-localization (nuclear dots), reporter assays The EMBO journal Medium 11060035
2002 GFI1 is required for granulocyte differentiation from myeloid precursors; Gfi1-/- mice are severely neutropenic and accumulate immature monocytic cells, and Gfi1-/- macrophages overproduce TNF, IL-10, and IL-1β upon LPS stimulation. Gene targeting (knockout mice), bone marrow differentiation assays with G-CSF, cytokine measurements Nature genetics High 11810106
2003 GFI1 represses ELA2 (encoding neutrophil elastase) through direct binding to its promoter; dominant-negative GFI1 zinc finger mutations in humans cause neutropenia with elevated ELA2 expression. Chromatin immunoprecipitation, gel-shift assay, reporter assays, RT-PCR of ELA2 in neutropenic patient samples Nature genetics High 12778173
2003 GFI1 is intrinsically required for neutrophil differentiation; Gfi1-/- progenitors accumulate at a stage expressing primary but not secondary/tertiary granule proteins, and re-expression of Gfi1 in sorted Gfi1-/- progenitors rescues neutrophil differentiation ex vivo in response to G-CSF. Gene targeting, bone marrow transplantation, ex vivo rescue by retroviral re-expression, RNA expression profiling Immunity High 12530980
2003 Chromatin immunoprecipitation in myeloid and T-lymphocyte cell lines identified 32 GFI1 binding sites across 16 target genes including cell-cycle regulators, transcription factors, and granulocyte-specific markers. Large-scale chromatin immunoprecipitation on 34 candidate genes, RT-PCR expression profiling Proceedings of the National Academy of Sciences of the United States of America High 12721361
2003 GFI1 associates with ETO (MTG8) and HDAC1, HDAC2, and HDAC3 in vivo; GFI1 and GFI1B localize to nuclear matrix-associated punctate subnuclear structures together with ETO, and transcriptional repression by GFI1 is TSA-sensitive. Co-immunoprecipitation in mammalian cells, nuclear matrix fractionation, co-localization imaging, TSA inhibitor treatment Journal of cellular biochemistry Medium 12874834
2003 GFI1 is required for inner ear hair cell differentiation and survival; Gfi1-/- mice initially specify hair cells but cochlear hair cells degenerate through apoptosis, and outer hair cells aberrantly express neuronal markers. Gfi1 knockout mouse analysis, immunohistochemistry, scanning electron microscopy, TUNEL apoptosis assay Development (Cambridge, England) High 12441305
2004 GFI1 restricts proliferation of hematopoietic stem cells (HSCs); Gfi1-/- HSCs show elevated BrdU incorporation and cell-cycle entry, and are functionally compromised in competitive repopulation and serial transplantation assays. BrdU incorporation, cell-cycle analysis, competitive repopulation and serial transplantation assays, ES cell chimaeras Nature High 15457180
2004 GFI1 regulates HSC self-renewal and engraftment; Gfi1-/- mice have reduced HSC frequency and CLPs, Gfi1-/- bone marrow shows impaired long-term reconstituting ability and increased HSC cycling, demonstrating a cell-autonomous requirement. Knockout mouse analysis, bone marrow transplantation, competitive long-term reconstitution assays, cell-cycle analysis The EMBO journal High 15385956
2004 GFI1 directly represses its own promoter through conserved cis-element binding sites, establishing an autoregulatory negative feedback loop; GFI1B can also repress the Gfi1 gene in trans. ChIP in primary thymocytes, reporter assays with Gfi1 promoter constructs, GFI1 transgenic silencing of Gfi1:GFP knock-in allele Nucleic acids research High 15131254
2004 GFI1 autoregulates its own expression; Gfi1 gene occupies its own promoter in thymocytes and Gfi1 protein represses its own transcription in vitro. ChIP in thymocytes, reporter assays, GFP knock-in reporter mouse The Journal of biological chemistry High 15252036
2004 GFI1 is a downstream transcriptional target of Pou4f3 in inner ear hair cells; loss of Pou4f3 reduces Gfi1 expression and outer hair cell degeneration in Pou4f3 mutants phenocopies Gfi1-/- outer hair cell degeneration. Microarray gene expression profiling, RT-PCR, in situ hybridization, immunohistochemistry, scanning electron microscopy comparing Pou4f3 and Gfi1 mutants Human molecular genetics Medium 15254021
2005 GFI1 recruits histone lysine methyltransferase G9a and HDAC1 to target gene promoters (including p21Cip/WAF1) to establish repressive chromatin; endogenous GFI1 co-localizes with G9a, HDAC1, and H3K9me2; Gfi1 silencing reverses G9a/HDAC1 recruitment and de-represses p21. Co-immunoprecipitation, ChIP for H3K9me2, G9a and HDAC1 occupancy; siRNA knockdown with RT-PCR; co-localization imaging Molecular and cellular biology High 16287849
2005 GFI1 functions downstream of Math1 (Atoh1) in the intestinal secretory lineage to select goblet/Paneth versus enteroendocrine progenitors; Gfi1-/- mice lack Paneth cells, have fewer goblet cells, and supernumerary enteroendocrine cells. Gfi1 knockout mouse analysis, intestinal histology, gene expression analysis, genetic epistasis with Math1 Genes & development High 16230531
2005 The AXH domain of Ataxin-1 interacts with GFI1 (and the Drosophila ortholog Senseless); overexpression of Ataxin-1 reduces GFI1/Senseless protein levels in Purkinje cells, and deletion of the AXH domain abolishes this effect. Protein interaction assays, co-immunoprecipitation (Drosophila and mammalian), Drosophila genetics, mouse Purkinje cell immunohistochemistry Cell High 16122429
2006 GFI1 physically interacts with PU.1 protein and represses PU.1-dependent transcription; this repression blocks PU.1-induced macrophage differentiation. Genetic reduction of PU.1 (Pu.1+/-) partially rescues the Gfi1-/- mixed myeloid phenotype. Co-immunoprecipitation, reporter assays, retroviral expression in hematopoietic progenitors, Gfi1/PU.1 compound mutant mice The Journal of biological chemistry High 17197705
2006 GFI1 directly interacts with the splice factor U2AF26 and antagonizes U2AF26-mediated CD45 exon exclusion, thereby promoting production of the more active CD45RB isoform versus CD45RO; loss of Gfi1 favors CD45RO production. Co-immunoprecipitation, T-cell splicing assays, Gfi1-/- mouse T cells, isoform-specific RT-PCR Nature immunology High 16819553
2007 GFI1 and GFI1B recruit the CoREST corepressor, histone demethylase LSD1, and HDACs 1 and 2 via their SNAG repression domain; GFI1B recruits these cofactors to target gene promoters in vivo; LSD1 depletion de-represses GFI1 targets with increased H3K4 methylation. Purification of GFI1B complexes by affinity/mass spectrometry, co-immunoprecipitation, ChIP for LSD1/CoREST/H3K4me at target promoters, siRNA knockdown, erythroid/megakaryocytic/granulocytic differentiation assays Molecular cell High 17707228
2007 GFI1 interacts with PRDM5 (a PR-domain tumor suppressor) identified by yeast two-hybrid; both co-regulate overlapping sets of hematopoiesis-associated genes by recruiting G9a and class I HDACs. Yeast two-hybrid, ChIP, reporter assays, siRNA knockdown Molecular and cellular biology Medium 17636019
2007 GFI1 directly represses CXCR4 expression in myeloid cells by binding to sequences upstream of the CXCR4 gene, reducing myeloid cell responses to SDF-1; G-CSF promotes Gfi1 expression, linking Gfi1 to G-CSF-induced granulocyte mobilization. ChIP, reporter assays, luciferase assay, CXCR4 flow cytometry, migration assays in Gfi1-/- cells Blood High 17596540
2008 During viral infection, GFI1 and GABPα have opposing functions at the Il7ra promoter: GFI1 represses IL-7Rα expression by antagonizing GABPα binding and recruiting HDAC1 to deacetylate the Il7ra promoter, while GABPα promotes hyperacetylation and IL-7Rα expression. Viral infection of mice, ChIP for histone acetylation and transcription factor occupancy, Gfi1-/- and GABPα-/- T cells Journal of immunology High 18390712
2008 GFI1 promotes GATA3 protein stability in Th2 cells; Gfi1-/- Th2 cells show enhanced ubiquitin/proteasome-dependent GATA3 degradation, and GATA3 overexpression rescues Gfi1-/- Th2 cell function. Gfi1-/- conditional mouse T cells, Western blot for GATA3 protein levels, proteasome inhibition, retroviral GATA3 rescue The Journal of biological chemistry Medium 18701459
2009 TGF-β downregulates GFI1 expression in CD4 T cells, and GFI1 directly represses the Il17a/Il17f loci and intron 1 of Cd103 by recruiting the LSD1 repressive complex; Gfi1-/- Th2 cells show H3K4me3 at the Rorc, Il23r, and Cd103 loci. ChIP for GFI1-LSD1 complex at Il17a/f loci and Cd103, H3K4me3 ChIP in Gfi1-/- cells, conditional knockout mice, EAE model The Journal of experimental medicine High 19188499
2009 GFI1 represses CDKN2B (p15INK4B) not by direct DNA binding but by interacting with Miz-1, which recruits GFI1 to the CDKN2B core promoter; GFI1 and c-Myc collaborate through Miz-1 to repress CDKN2B. Co-immunoprecipitation, ChIP, reporter assays, siRNA knockdown, Gfi1-/- bone marrow cells Proceedings of the National Academy of Sciences of the United States of America High 19164764
2009 GFI1 controls microRNA expression during myelopoiesis; Gfi1-/- mice and GFI1-mutant SCN patient cells show deregulated miR-21 and miR-196b, and co-expression of both miRNAs completely blocks G-CSF-induced granulopoiesis. miRNA profiling, flow cytometry, colony assays, retroviral miRNA overexpression/depletion in bone marrow cells Blood High 19278956
2009 PFAAP5 (N4BP2L2) is a novel protein that interacts with both GFI1 and neutrophil elastase; PFAAP5 enables neutrophil elastase to potentiate GFI1-mediated repression of target genes, delineating a feedback pathway regulating neutrophil production. Yeast two-hybrid, reporter assays, RNA interference, ChIP, HSC differentiation assays Molecular and cellular biology Medium 19506020
2010 GFI1 transcription factor promotes expression of RasGRP1, which is required for G-CSF to activate Erk1/2 signaling (but not STAT1/3); Gfi1-null myeloid cells are selectively defective in Erk1/2 activation by G-CSF, and RasGRP1 re-expression rescues both Erk activation and neutrophil maturation. Gfi1-/- mouse bone marrow, retroviral transduction, Western blot for Erk1/2/STAT phosphorylation, neutrophil differentiation assays Blood High 20203268
2010 GFI1 binds to Id2 promoter at three conserved regions and represses Id2 transcription; increased Id2 in Gfi1-/- progenitors contributes to B-cell and myeloid developmental defects, as Id2 knockdown or Id2 heterozygosity partially rescues these defects. ChIP, reporter assays, siRNA/genetic Id2 reduction in Gfi1-/- mice, flow cytometry of B-cell and myeloid progenitor populations Blood High 20453161
2010 GFI1 interacts with p65 (RelA) NF-κB subunit upon LPS stimulation and inhibits p65-mediated transcriptional activation by interfering with p65 binding to target gene promoters; Gfi1-/- macrophages show abnormally high TNF-α and other p65 target gene expression with increased p65 promoter occupancy. Co-immunoprecipitation, ChIP for p65 promoter occupancy, Gfi1-/- primary macrophages, LPS stimulation, mRNA quantification Molecular and cellular biology High 20547752
2010 GFI1 represses CDKN1A (p21Cip1) through interaction with Miz-1 at the core promoter in a DNA-binding-independent manner; GFI1 and c-Myc form a ternary complex on the CDKN1A promoter; GFI1 knockdown increases p21 levels and reduces proliferation. Co-immunoprecipitation, ChIP, reporter assays, siRNA knockdown Oncogene High 20190815
2010 Solution NMR structure of GFI1 zinc fingers 3–5 bound to consensus DNA shows that zinc fingers bind in the major groove (not minor groove); ZF4 and ZF5 form base-specific hydrogen bonds (Asn382, Gln379, Asp354) with invariant adenines and cytosine in the AATC core. Multidimensional NMR structure determination of ZF3-5/DNA complex Journal of molecular biology High 20153336
2010 GABP (GABPα) transcription factor binds and activates the Gfi1 promoter and is required for Gfi1 expression in myeloid cells; transduction of Gfi1 into Gabpa-null bone marrow partially rescues myeloid differentiation defects. Conditional Gabpa knockout mice, ChIP for GABPα at Gfi1 promoter, retroviral rescue with Gfi1, colony assays Blood High 21705494
2010 GFI1 protein levels in monocytes are regulated post-translationally by the ubiquitin-proteasome system; Gfi1 mRNA is low in monocytes but protein accumulates due to diminished proteasomal turnover; ChIP shows Gfi1 protein occupies granulocyte-specific gene promoters in monocytes correlating with their repression. Proteasome inhibitor treatment, ubiquitination assays, Western blot, ChIP in primary monocytes and granulocytes Blood High 16888099
2007 The ubiquitin ligase Triad1 interacts with the DNA-binding domain of GFI1 and inhibits its ubiquitination, prolonging GFI1 half-life; Triad1 knockdown increases GFI1 ubiquitination and destabilization. Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, half-life measurement, proliferation assays Blood High 17646546
2018 LSD1 inhibitors disrupt the physical interaction between LSD1/RCOR1 and the GFI1 SNAG domain at a discrete set of enhancers near myeloid differentiation transcription factor genes; physical separation of LSD1/RCOR1 from GFI1 (not LSD1 demethylase activity per se) is required for drug-induced differentiation in AML. Co-immunoprecipitation with LSD1 inhibitors, ChIP-seq for LSD1/GFI1/RCOR1/H3K27ac, demethylase-dead mutant rescue, AML differentiation assays Cell reports High 29590629
2019 GFI1 physically associates with LSD1 in medulloblastoma; GFI1 proteins unable to recruit LSD1 fail to drive tumorigenesis; genetic ablation of Lsd1 markedly impairs GFI1-driven tumor growth in vivo. Co-immunoprecipitation, GFI1-LSD1 interaction mutant constructs, Lsd1 conditional knockout in GFI1-driven medulloblastoma mouse model, pharmacological LSD1 inhibition Nature communications High 30659187
2016 SMYD2 methylates GFI1 at lysine-8 (K8) within the SNAG domain; K8 methylation is required for LSD1 recruitment and transcriptional repression; methylation-defective GFI1 retains H3K4me2 at target promoters and fails to rescue GFI1 depletion phenotypes in zebrafish or support lymphoid leukemia cell growth. In vitro methylation assay, mutagenesis of GFI1 K8, ChIP for H3K4me2, zebrafish rescue experiments, lymphoid leukemia cell growth assays The Biochemical journal High 27480105
2018 GFI1 interacts with the arginine methyltransferase PRMT1 and enables PRMT1 to bind and methylate its substrates MRE11 and 53BP1, facilitating their function in the DNA damage response; GFI1 deletion causes hypersensitivity to ionizing radiation. Co-immunoprecipitation of GFI1-PRMT1-MRE11-53BP1, in vitro methylation assay, GFI1-/- T cells irradiation sensitivity, DNA damage repair assays Nature communications High 29651020
2019 GSK3β phosphorylates GFI1 at S94/S98, triggering its interaction with FBXW7 and subsequent SCFFBXW7-mediated ubiquitination and proteasomal degradation; a non-degradable S94A/S98A GFI1 mutant is more potent in driving gastric cancer cell proliferation. Phosphorylation assays, co-immunoprecipitation, ubiquitination assays, GSK3β inhibitor treatment, mutagenesis (S94A/S98A), tumor growth assays Cancer research High 31289136
2012 GFI1 acts as a transcriptional repressor of CD39 and CD73 ectonucleotidase genes in Th17 cells by directly binding their promoters; TGF-β-driven downregulation of GFI1 is essential for ectonucleotidase expression and the immunosuppressive fate of Th17 cells. ChIP for GFI1 at CD39/CD73 promoters, GFI1 knockdown/overexpression, Th17 differentiation assays, adoptive transfer tumor model Immunity High 22406269
2010 In Gfi1-/- intestinal epithelium, Gfi1 is required to stably repress Neurog3 in mucous and Paneth cell lineages; in its absence, these lineage cells aberrantly activate Neurog3 and undergo cellular reprogramming into the enteroendocrine lineage. Gfi1-/- mouse intestinal epithelium analysis, Neurog3 immunofluorescence, lineage tracing of mucous/Paneth cells Developmental biology Medium 20599897
2010 GFI1(36N) variant protein has a different subnuclear localization than GFI1(36S); AML1/ETO interacts and co-localizes with GFI1(36S) in the nucleus and inhibits its repressor activity, but does not co-localize with GFI1(36N) and cannot inhibit it, suggesting variant-specific regulation in AML. Subnuclear localization imaging, co-immunoprecipitation, reporter assays for repressor activity, patient cohort genotyping Blood Medium 20075157
2013 GFI1 is required for ILC2 development and directly activates Il1rl1 (encoding ST2/IL-33 receptor); Gfi1-deficient ILC2 cells show impaired IL-33 responsiveness, reduced GATA-3 expression, and a dysregulated genome-wide effector state. Gfi1-/- mouse ILC2 analysis, ChIP for GFI1 at Il1rl1, helminth infection and allergen challenge models Nature immunology High 24141388
2016 Gfi1 represses Tbx21, Eomes, and Runx2 gene loci in T cells, reducing H3K4 methylation in part by modulating LSD1 recruitment; Gfi1-deficient CD4 T cells spontaneously develop Th1-type identity without requirement for IL-12 or IFN-γ. ChIP for GFI1 and H3K4me at Tbx21/Eomes/Runx2 loci, Gfi1-/- CD4 T cells, cytokine-neutralization experiments, DTH model Immunology Medium 26749286

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells. Nature 425 15457180
2007 Epigenetic regulation of hematopoietic differentiation by Gfi-1 and Gfi-1b is mediated by the cofactors CoREST and LSD1. Molecular cell 345 17707228
2003 Intrinsic requirement for zinc finger transcription factor Gfi-1 in neutrophil differentiation. Immunity 312 12530980
2003 Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2. Nature genetics 290 12778173
2012 Stat3 and Gfi-1 transcription factors control Th17 cell immunosuppressive activity via the regulation of ectonucleotidase expression. Immunity 278 22406269
2012 PI3K-Akt-mTORC1-S6K1/2 axis controls Th17 differentiation by regulating Gfi1 expression and nuclear translocation of RORγ. Cell reports 271 22832227
1996 Gfi-1 encodes a nuclear zinc finger protein that binds DNA and functions as a transcriptional repressor. Molecular and cellular biology 271 8754800
2002 Inflammatory reactions and severe neutropenia in mice lacking the transcriptional repressor Gfi1. Nature genetics 262 11810106
2005 Gfi1 functions downstream of Math1 to control intestinal secretory cell subtype allocation and differentiation. Genes & development 256 16230531
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