GFI1

Summary

GFI1 (growth factor independent 1 transcriptional repressor, HGNC:4237) is a protein-coding gene on chromosome 1p22.1, encoding Zinc finger protein Gfi-1 (Q99684). Transcription repressor essential for hematopoiesis.

This gene encodes a nuclear zinc finger protein that functions as a transcriptional repressor. This protein plays a role in diverse developmental contexts, including hematopoiesis and oncogenesis. It functions as part of a complex along with other cofactors to control histone modifications that lead to silencing of the target gene promoters. Mutations in this gene cause autosomal dominant severe congenital neutropenia, and also dominant nonimmune chronic idiopathic neutropenia of adults, which are heterogeneous hematopoietic disorders that cause predispositions to leukemias and infections. Multiple alternatively spliced variants, encoding the same protein, have been identified for this gene.

Source: NCBI Gene 2672 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neutropenia, severe congenital, 2, autosomal dominant (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 766 total — 1 pathogenic
• Phenotypes (HPO): 33
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• Transcription factor: yes — 60 downstream targets (CollecTRI)
• MANE Select transcript: NM_005263

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4237
Approved symbol	GFI1
Name	growth factor independent 1 transcriptional repressor
Location	1p22.1
Locus type	gene with protein product
Status	Approved
Aliases	GFI1A, GFI-1
Ensembl gene	ENSG00000162676
Ensembl biotype	protein_coding
OMIM	600871
Entrez	2672

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 9 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000294702, ENST00000370332, ENST00000427103, ENST00000483490, ENST00000696667, ENST00000696668, ENST00000696669, ENST00000696670, ENST00000696671, ENST00000881421, ENST00000881422

RefSeq mRNA: 3 — MANE Select: NM_005263 NM_001127215, NM_001127216, NM_005263

CCDS: CCDS30773

Canonical transcript exons

ENST00000294702 — 7 exons

Exon	Start	End
ENSE00001067549	92478588	92478753
ENSE00001067552	92480348	92480485
ENSE00001144597	92480601	92481088
ENSE00001144606	92482864	92483046
ENSE00001379885	92486726	92486925
ENSE00001817536	92473043	92476207
ENSE00003524540	92483373	92483586

Expression profiles

Bgee: expression breadth ubiquitous, 153 present calls, max score 87.84.

FANTOM5 (CAGE): breadth broad, TPM avg 4.8931 / max 303.2525, expressed in 407 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
13273	1.8760	273
13268	1.3303	162
13274	0.5261	182
13272	0.3606	178
13270	0.2174	102
13271	0.1978	113
13269	0.1629	60
13266	0.1078	33
13265	0.0809	39
13267	0.0332	14

Top tissues by expression

283 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	87.84	gold quality
bone marrow	UBERON:0002371	86.83	gold quality
bone marrow cell	CL:0002092	86.75	gold quality
trabecular bone tissue	UBERON:0002483	85.74	gold quality
body of pancreas	UBERON:0001150	81.37	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.21	gold quality
superficial temporal artery	UBERON:0001614	77.07	gold quality
thymus	UBERON:0002370	77.04	gold quality
blood	UBERON:0000178	76.46	gold quality
lymph node	UBERON:0000029	75.26	gold quality
spleen	UBERON:0002106	75.18	gold quality
vermiform appendix	UBERON:0001154	74.25	gold quality
epithelium of nasopharynx	UBERON:0001951	74.13	silver quality
nasopharynx	UBERON:0001728	74.12	silver quality
rectum	UBERON:0001052	73.73	gold quality
pancreas	UBERON:0001264	72.90	gold quality
secondary oocyte	CL:0000655	72.83	silver quality
small intestine Peyer’s patch	UBERON:0003454	72.69	gold quality
mucosa of transverse colon	UBERON:0004991	72.40	gold quality
caecum	UBERON:0001153	71.63	gold quality
small intestine	UBERON:0002108	71.35	gold quality
gall bladder	UBERON:0002110	69.19	gold quality
vastus lateralis	UBERON:0001379	69.10	gold quality
jejunal mucosa	UBERON:0000399	68.95	silver quality
duodenum	UBERON:0002114	68.85	gold quality
mucosa of sigmoid colon	UBERON:0004993	67.76	silver quality
quadriceps femoris	UBERON:0001377	67.66	gold quality
transverse colon	UBERON:0001157	67.56	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	67.36	gold quality
myocardium	UBERON:0002349	67.30	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.16

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

60 targets.

Target	Regulation
ABL1
ADAM2
ARIH2
BAX	Repression
BIRC5	Repression
CD8A
CDKN1A	Unknown
CDKN2B	Repression
CSF1	Repression
CSF1R
CSF3
CXCR4	Repression
CYP27B1	Repression
EGR2	Repression
ELANE	Unknown
ENTPD1
GATA1	Activation
GFI1
GFI1B	Unknown
GHR
GUCY1B1	Unknown
HOXA9
ID2
IL13	Repression
IL17A	Activation
IL17F	Activation
IL2
IL5	Activation
IL7
IL7R	Repression

JASPAR motifs

Motif	Name	Family
MA0038.2	GFI1	More than 3 adjacent zinc fingers
MA0038.3	GFI1	More than 3 adjacent zinc fingers

JASPAR matrix evidence (PMIDs): PMID:8754800

Upstream regulators (CollecTRI, top): ATOH7, CEBPA, CEBPD, CEBPE, EBF1, EGR2, ERG, FOXC1, GABPA, GATA2, GFI1, GFI1B, IRF6, MEIS1, NAB2, PRDM5, RELA, RUNX1, RUNX2, SPI1, STAT1, STAT5A, STAT6, TAL1, TCF3, TP53, ZBTB16, ZNF91

miRNA regulators (miRDB)

87 targeting GFI1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-577	99.78	69.13	2479

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2 (PMID:12778173)
• role for auto- and trans-regulation of Gfi1 by GFI1 and GFI1B in maintaining the normal expression patterns of Gfi1 (PMID:15131254)
• GFI1 in prostate cancer cells acts as a repressor of 25-hydroxyvitamin D 1-alpha hydroxylase gene. (PMID:15947108)
• findings highlight the role of epigenetics in the regulation of development and oncogenesis by Gfi1 (PMID:16287849)
• Gfi1 levels are regulated by the ubiquitin-proteasome system. It binds the promoters of several granulocyte-specific genes in primary monocytes. This correlated with low expression of these genes in monocytes compared with granulocytes. (PMID:16888099)
• GFI1 may play a significant role in the down regulation of endogenous production of 1,25D in prostate cancer cells and could provide a novel insight to future diagnosis and treatment (PMID:17207994)
• the interaction between ETS1 and GFI1 facilitates their binding to specific sites on the Bax promoter and represses Bax expression (PMID:17213822)
• Decreased Gfi-1 levels in our SGD patient, together with the mutant C/EBPepsilon, block secondary granules proteins expression, thereby contributing to the underlying etiology of the disease in our patient. (PMID:17244686)
• Results identify PRDM5, which acts as a sequence-specific, DNA binding transcription factor that targets hematopoiesis-associated protein-coding and microRNA genes, some of which are targets of Gfi1. (PMID:17636019)
• The fine-tuning of Gfi1 protein levels regulated by Triad1 defines an unexpected role for this protein in hematopoiesis. (PMID:17646546)
• The measurement of CD34 and GFI1 mRNA expressions could be useful as a diagnostic and prognostic marker for myelodysplastic syndrome. (PMID:18371060)
• the T cell receptor-mediated induction of Gfi1 controls Th2 cell differentiation through the regulation of GATA3 protein stability (PMID:18701459)
• Ajuba is utilized as a corepressor selectively on Gfi1 target genes (PMID:18805794)
• These results reveal novel contributions of MTGR1 and GFI1 to the regulation of neurite outgrowth and identify novel repressors of integrin-dependent neurite outgrowth. (PMID:19026687)
• data reveal a mechanism of transcriptional repression by Gfi-1 and may have important implications for understanding the roles of Gfi-1 in normal development and tumorigenesis (PMID:19164764)
• Data suggest that expression of PFAAP5 allows neutrophil elastase to potentiate the repression of Gfi1 target genes. (PMID:19506020)
• Gfi1 mRNA level in both the mononuclear cells and purified CD34(+) cells from CML were significantly higher as measured by quantitative real-time PCR. (PMID:19887785)
• a variant allele of GFI1 (GFI1(36N)) is associated with acute myeloid leukemia (AML) in white subjects (PMID:20075157)
• An analysis and fine mapping of GFI-EVI5-RPL5-FAM69A locus, genotyping eight Tag-single nucleotide polymorphisms in 732 multiple sclerosis patients and 974 controls from Spain, was performed. (PMID:20087403)
• Studies indicate that Gfi1 is central to several transcriptional circuits whose dysregulation leads to abnormal or malignant hematopoiesis. (PMID:20571393)
• GFI1 may play an important role in leukemia, especially in CML incidence and progression. (PMID:20723283)
• GFI-1 expression is upregulated in leukemia patients and may contribute to leukemogenesis. (PMID:20723286)
• Data suggest that Gfi1 may have an important role in prolonged multiple myeloma (MM)-induced osteoblast (OB) suppression and provide a new therapeutic target for MM bone disease. (PMID:22042697)
• Our data suggest that the presence of a GFI136N variant allele induces a preleukemic state in myeloid precursors by deregulating the expression of Hoxa9 and other AML-related genes. (PMID:22932805)
• The competition for this binding site inhibits the expression of HOXA9 and induces different transcriptional outcomes, which suggests a new direction for investigation of the mechanism underlying targeted therapy of malignant gliomas. (PMID:23466061)
• Studies indicate that Gfi1 recruits LSD1 to p53 and dampens its activity by de-methylating p53 at C-terminal lysines to prevent immediate apoptosis. (PMID:23528269)
• the expression of Gfi-1 contributes to SOCS1 silencing in AML cells through epigenetic modification, and suppression of histone methyltransferase can provide new insight in AML therapy. (PMID:24018353)
• GFI1 is repressed by p53 (PMID:24023884)
• Data shows that MYB regulates the expression of endogenous human GFI1. (PMID:24121275)
• Lymphoid progenitor cells from childhood acute lymphoblastic leukemia are functionally deficient and express high levels of the transcriptional repressor Gfi-1. (PMID:24198842)
• results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate ’enhancer hijacking’ as an efficient mechanism driving oncogene activation in a childhood cancer (PMID:25043047)
• miR-495 directly interacts with the Gfi1 3’UTR to regulate Gfi1 at a post-transcriptional level and the expression level of miR-495 is inversely correlated with the Gfi1 protein level in medulloblastoma specimens. (PMID:26160036)
• Gfi1 acts as a transcriptional repressor by recruiting histone-modifying enzymes to promoters and enhancers of target genes. Mutations of the C-terminal zinc finger domain causes congenital neutropenia. It may be involved in leukemia and lymphoma. Review. (PMID:26447191)
• GFI1(36S) homozygous patients exhibited a sustained response to treatment with hypomethylating agents, whereas GFI1(36N) patients had a poor sustained response to this therapy. Because allele status of GFI1(36N) is readily determined using basic molecular techniques, we propose inclusion of GFI1(36N) status in future prospective studies for MDS patients to better predict prognosis and guide therapeutic decisions. (PMID:27080012)
• Gfi1 gene expression is regulated by cytokines in activated T cells. (PMID:27143377)
• Maternal-smoking sensitive CpG sites in newborns were significantly associated with cg18146737 SNP located proximal to GFI1. (PMID:27403598)
• combination of the sequence-specific and nonspecific DNA-binding modes of SATB1 should be advantageous in a search for target loci during transcriptional regulation (PMID:27480105)
• In this study, the influence of prenatal smoking exposure on the childrens’ DNA methylation state of a CpG island located upstream of the promoter of the growth factor independent 1 (GFI1) gene was analyzed. Significant hypomethylation was observed in this CpG island in SIDS cases with cigarette smoke exposure compared to non-exposed cases. (PMID:27677632)
• Simvastatin attenuates the tumor-associated macrophage mediated gemcitabine resistance of PDAC by blocking the TGF-beta1/Gfi-1 axis. (PMID:27840243)
• GFI1 downregulation promotes inflammation-linked metastasis of colorectal cancer. (PMID:28387757)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	gfi1ab	ENSDARG00000044457
mus_musculus	Gfi1	ENSMUSG00000029275
rattus_norvegicus	Gfi1	ENSRNOG00000002042
drosophila_melanogaster	sens	FBGN0002573

Paralogs (28): ZNF280C (ENSG00000056277), ZBTB25 (ENSG00000089775), PRDM13 (ENSG00000112238), BCL6 (ENSG00000113916), FEZF1 (ENSG00000128610), ZBTB46 (ENSG00000130584), PRDM12 (ENSG00000130711), ZNF280D (ENSG00000137871), NACC2 (ENSG00000148411), FEZF2 (ENSG00000153266), ZBTB7B (ENSG00000160685), NACC1 (ENSG00000160877), BCL6B (ENSG00000161940), GFI1B (ENSG00000165702), ZBTB49 (ENSG00000168826), ZNF280A (ENSG00000169548), ZNF581 (ENSG00000171425), ZNF524 (ENSG00000171443), ZBTB26 (ENSG00000171448), ZBTB21 (ENSG00000173276), ZNF683 (ENSG00000176083), ZBTB33 (ENSG00000177485), ZBTB3 (ENSG00000185670), ZBTB6 (ENSG00000186130), ZBTB14 (ENSG00000198081), ZBTB12 (ENSG00000204366), ZNF580 (ENSG00000213015), ZNF280B (ENSG00000275004)

Protein

Protein identifiers

Zinc finger protein Gfi-1 — Q99684 (reviewed: Q99684)

Alternative names: Growth factor independent protein 1, Zinc finger protein 163

All UniProt accessions (4): A0A8Q3SIQ6, A0A8Q3SIW2, A0A8Q3SJ16, Q99684

UniProt curated annotations — full annotation on UniProt →

Function. Transcription repressor essential for hematopoiesis. Functions in a cell-context and development-specific manner. Binds to 5’-TAAATCAC[AT]GCA-3’ in the promoter region of a large number of genes. Component of several complexes, including the EHMT2-GFI1-HDAC1, AJUBA-GFI1-HDAC1 and RCOR-GFI-KDM1A-HDAC complexes, that suppress, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. Regulates neutrophil differentiation, promotes proliferation of lymphoid cells, and is required for granulocyte development. Inhibits SPI1 transcriptional activity at macrophage-specific genes, repressing macrophage differentiation of myeloid progenitor cells and promoting granulocyte commitment. Mediates, together with U2AF1L4, the alternative splicing of CD45 and controls T-cell receptor signaling. Regulates the endotoxin-mediated Toll-like receptor (TLR) inflammatory response by antagonizing RELA. Cooperates with CBFA2T2 to regulate ITGB1-dependent neurite growth. Controls cell-cycle progression by repressing CDKNIA/p21 transcription in response to TGFB1 via recruitment of GFI1 by ZBTB17 to the CDKNIA/p21 and CDKNIB promoters. Required for the maintenance of inner ear hair cells. In addition to its role in transcription, acts as a substrate adapter for PRMT1 in the DNA damage response: facilitates the recognition of TP53BP1 and MRE11 substrates by PRMT1, promoting their methylation and the DNA damage response.

Subunit / interactions. Interacts with U2AF1L4. Component of RCOR-GFI-KDM1A-HDAC complexes. Interacts directly with RCOR1, KDM1A and HDAC2. Also interacts with HDAC1. Interacts (via the zinc-finger domain) with ARIH2; the interaction prevents GFI1 ubiquitination and proteasomal degradation. Interacts with PIAS3; the interaction relieves the inhibitory effect of PIAS3 on STAT3-mediated transcriptional activity. Forms a complex with EHMT2 and HDAC1 to promote ‘Lys-9’ dimethylation of H3 (H3K9Me2) and repress expression of target genes. Interacts directly with EHMT2. Component of the GFI1-AJUBA-HDAC1 repressor complex. Interacts directly with AJUBA (via ITS LIM domains); the interaction results in the HDAC-dependent corepression of a subset of GFI1 target genes and, occurs independently of the SNAG domain. Interacts with SPI1; the interaction inhibits SPI1 transcriptional activity targeted at macrophage-specific genes, repressing macrophage differentiation of myeloid progenitor cells and promoting granulocyte commitment. Interacts with RUNX1T1; the interaction represses HDAC-mediated transcriptional activity. Interacts with RELA; the interaction occurs on liposaccharide (LPS) stimulation and controls RELA DNA binding activity and regulates endotoxin-mediated TOLL-like receptor inflammatory response. Interacts (via the C-terminal zinc fingers) with ZBTB17; the interaction results in the recruitment of GFI1 to the CDKN1A/p21 and CDKN1B promoters and repression of transcription.

Subcellular location. Nucleus.

Post-translational modifications. Ubiquitinated. Ubiquitination and degradation by the proteasome is inhibited by the ubiquitin ligase, ARIH2.

Disease relevance. Neutropenia, severe congenital 2, autosomal dominant (SCN2) [MIM:613107] A disorder of hematopoiesis characterized by maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections. The disease is caused by variants affecting the gene represented in this entry. Dominant nonimmune chronic idiopathic neutropenia of adults (NI-CINA) [MIM:607847] Relatively mild form of neutropenia diagnosed in adults, but predisposing to leukemia in a subset of patients. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Zinc fingers 3, 4 and 5 are required for DNA-binding and for interaction with SPI1. The SNAG domain of GFIs is required for nuclear location and for interaction with some corepressors.

Induction. Down-regulated by TGFB1.

RefSeq proteins (3): NP_001120687, NP_001120688, NP_005254* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013087	Znf_C2H2_type	Domain
IPR036236	Znf_C2H2_sf	Homologous_superfamily

Pfam: PF00096

UniProt features (22 total): zinc finger region 6, sequence conflict 6, sequence variant 3, region of interest 3, modified residue 2, chain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99684-F1	58.33	0.29

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 20, 56

Mutagenesis-validated functional residues (1):

Position	Phenotype
2	abrogates transcriptional repression.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9616222	Transcriptional regulation of granulopoiesis

MSigDB gene sets: 460 (showing top): RNGTGGGC_UNKNOWN, TGCGCANK_UNKNOWN, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, CHIARETTI_T_ALL_REFRACTORY_TO_THERAPY, GCANCTGNY_MYOD_Q6, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, BHATI_G2M_ARREST_BY_2METHOXYESTRADIOL_DN, GOBP_NEGATIVE_REGULATION_OF_STEROID_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, GOBP_NEUROGENESIS, TAL1ALPHAE47_01, MODULE_308, AAAYRNCTG_UNKNOWN

GO Biological Process (12): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of transcription by RNA polymerase II (GO:0006357), DNA damage response (GO:0006974), negative regulation of vitamin D biosynthetic process (GO:0010957), negative regulation of neuron projection development (GO:0010977), obsolete negative regulation of NF-kappaB transcription factor activity (GO:0032088), regulation of toll-like receptor signaling pathway (GO:0034121), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of interleukin-6-mediated signaling pathway (GO:0070105), cellular response to lipopolysaccharide (GO:0071222), double-strand break repair via homologous recombination (GO:0000724), negative regulation of double-strand break repair via homologous recombination (GO:2000042)

GO Molecular Function (10): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription factor activity (GO:0003700), zinc ion binding (GO:0008270), enzyme-substrate adaptor activity (GO:0140767), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (4): nucleus (GO:0005634), nuclear matrix (GO:0016363), nuclear body (GO:0016604), transcription repressor complex (GO:0017053)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	3
transcription by RNA polymerase II	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
regulation of transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
cellular response to stress	1
negative regulation of steroid biosynthetic process	1
vitamin D biosynthetic process	1
negative regulation of vitamin metabolic process	1
regulation of vitamin D biosynthetic process	1
regulation of neuron projection development	1
neuron projection development	1
negative regulation of cell projection organization	1
toll-like receptor signaling pathway	1
regulation of pattern recognition receptor signaling pathway	1
DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
positive regulation of cytokine-mediated signaling pathway	1
interleukin-6-mediated signaling pathway	1
regulation of interleukin-6-mediated signaling pathway	1
response to lipopolysaccharide	1
cellular response to molecule of bacterial origin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
recombinational repair	1
double-strand break repair	1
double-strand break repair via homologous recombination	1
regulation of double-strand break repair via homologous recombination	1
negative regulation of DNA recombination	1
negative regulation of double-strand break repair	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
cis-regulatory region sequence-specific DNA binding	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
transition metal ion binding	1
protein-macromolecule adaptor activity	1

Protein interactions and networks

STRING

2070 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GFI1	KDM1A	O60341	982
GFI1	HDAC1	Q13547	938
GFI1	POU4F3	Q15319	907
GFI1	EHMT2	Q96KQ7	867
GFI1	RCOR1	Q9UKL0	854
GFI1	ATXN1	P54253	846
GFI1	GATA1	P15976	843
GFI1	GATA2	P23769	836
GFI1	ELANE	P08246	767
GFI1	OCM2	P0CE71	758
GFI1	HDAC2	Q92769	748
GFI1	RUNX1	Q01196	734
GFI1	HAX1	O00165	727
GFI1	ATOH1	Q92858	727
GFI1	OCM	P0CE72	719

IntAct

35 interactions, top by confidence:

A	B	Type	Score
HDAC1	EHMT2	psi-mi:“MI:0914”(association)	0.840
GFI1	Ajuba	psi-mi:“MI:0915”(physical association)	0.540
GFI1	Ajuba	psi-mi:“MI:0403”(colocalization)	0.540
GFI1	PRDM5	psi-mi:“MI:0915”(physical association)	0.510
PRDM5	GFI1	psi-mi:“MI:0915”(physical association)	0.510
HDAC1	GFI1	psi-mi:“MI:0915”(physical association)	0.500
GFI1	HDAC1	psi-mi:“MI:0915”(physical association)	0.500
CHAF1A	GFI1	psi-mi:“MI:0915”(physical association)	0.460
GFI1	CHAF1A	psi-mi:“MI:0403”(colocalization)	0.460
GFI1	CHAF1A	psi-mi:“MI:0915”(physical association)	0.460
Ehmt2	GFI1	psi-mi:“MI:0915”(physical association)	0.400
ZBTB17	GFI1	psi-mi:“MI:0915”(physical association)	0.400
RELA	GFI1	psi-mi:“MI:0915”(physical association)	0.400
GFI1	RELA	psi-mi:“MI:0915”(physical association)	0.400
GFI1	U2AF1L4	psi-mi:“MI:0915”(physical association)	0.400
GFI1	PIAS3	psi-mi:“MI:0915”(physical association)	0.400
Spi1	GFI1	psi-mi:“MI:0915”(physical association)	0.400
SPI1	GFI1	psi-mi:“MI:0915”(physical association)	0.400
EHMT2	GFI1	psi-mi:“MI:0915”(physical association)	0.400
GFI1	EHMT2	psi-mi:“MI:0915”(physical association)	0.400
GFI1	TP53	psi-mi:“MI:0915”(physical association)	0.400
Limd1	GFI1	psi-mi:“MI:0915”(physical association)	0.370
GFI1	Limd1	psi-mi:“MI:0915”(physical association)	0.370
IL17F	GFI1	psi-mi:“MI:0915”(physical association)	0.370
TNFSF4	GFI1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (43): ZBTB17 (Affinity Capture-Western), GFI1 (Reconstituted Complex), GFI1 (Affinity Capture-Western), GFI1 (Affinity Capture-RNA), PRMT1 (Affinity Capture-MS), HDAC2 (Affinity Capture-MS), FBXW7 (Affinity Capture-MS), GFI1 (Affinity Capture-Western), FBXW7 (Affinity Capture-Western), CUL1 (Affinity Capture-Western), GFI1 (Biochemical Activity), FBXW7 (Reconstituted Complex), GFI1 (Positive Genetic), PIAS3 (Two-hybrid), PIAS3 (Reconstituted Complex)

ESM2 similar proteins: A0A2Z4LIS9, A2CE44, A6NFI3, E9PZZ1, O95201, P09066, P15863, P19622, P22091, P46099, P49640, P70338, P82976, P97503, P98168, P98169, Q05917, Q07120, Q13351, Q14549, Q14V87, Q15270, Q19A40, Q2QGD7, Q3SY56, Q3U133, Q58DK7, Q5DWN0, Q6IQX8, Q6NUN9, Q8C8V1, Q8NCA9, Q8TD94, Q8WUU4, Q924A2, Q92618, Q96RK0, Q99684, Q9BV97, Q9BYN7

Diamond homologs: O42409, O57415, O70237, O77459, P28166, P60319, P70338, Q07120, Q3UH06, Q5DWN0, Q5VTD9, Q6DCW1, Q92766, Q99684, A1L2U9, B1WAZ8, B1WBU4, G5EBU4, O60315, O62836, O73590, O97581, P08048, P17010, P17012, P20271, P31509, P36197, P37275, P39770, P39806, P39956, P50481, P52739, P53410, P56270, P56670, P56671, P61375, P61376

SIGNOR signaling

14 interactions.

A	Effect	B	Mechanism
GFI1	“down-regulates activity”	ETS1	binding
ETS1	“down-regulates activity”	GFI1	binding
GFI1	“down-regulates quantity by repression”	BAX	“transcriptional regulation”
GFI1	“down-regulates quantity by repression”	CYP27B1	“transcriptional regulation”
miR-155	“down-regulates quantity by repression”	GFI1	“post transcriptional regulation”
CEBPA	“up-regulates quantity by expression”	GFI1	“transcriptional regulation”
GFI1	up-regulates	Granulocyte_differentiation
GSK3B	“down-regulates quantity by destabilization”	GFI1	phosphorylation
SCF-FBW7	“down-regulates quantity by destabilization”	GFI1	polyubiquitination
EGR2	“down-regulates quantity by repression”	GFI1	“transcriptional regulation”
NAB2	“down-regulates quantity by repression”	GFI1	“transcriptional regulation”
GFI1	“down-regulates activity”	SPI1	binding
GFI1	“down-regulates quantity by repression”	EGR2	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

766 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	450
Likely benign	262
Benign	14

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
8739	NM_005263.5(GFI1):c.1145A>G (p.Asn382Ser)	Pathogenic

SpliceAI

810 predictions. Top by Δscore:

Variant	Effect	Δscore
1:92476203:CTCAC:C	acceptor_gain	1.0000
1:92476205:CAC:C	acceptor_gain	1.0000
1:92476216:A:AC	acceptor_gain	1.0000
1:92478586:A:AC	donor_gain	1.0000
1:92478587:C:CC	donor_gain	1.0000
1:92478751:TTC:T	acceptor_gain	1.0000
1:92478752:TC:T	acceptor_gain	1.0000
1:92478753:CC:C	acceptor_gain	1.0000
1:92478754:C:CC	acceptor_gain	1.0000
1:92480342:GCTTA:G	donor_loss	1.0000
1:92480344:TTACC:T	donor_loss	1.0000
1:92480345:TACCT:T	donor_loss	1.0000
1:92480346:A:T	donor_loss	1.0000
1:92480347:CCTG:C	donor_gain	1.0000
1:92480486:C:CA	acceptor_loss	1.0000
1:92480487:T:G	acceptor_loss	1.0000
1:92480595:CCTCA:C	donor_loss	1.0000
1:92480596:CTCA:C	donor_loss	1.0000
1:92480597:TCAC:T	donor_loss	1.0000
1:92480598:CAC:C	donor_loss	1.0000
1:92480599:ACCTT:A	donor_loss	1.0000
1:92480600:C:A	donor_loss	1.0000
1:92482858:TCCTA:T	donor_loss	1.0000
1:92482859:CCTA:C	donor_loss	1.0000
1:92482860:CTA:C	donor_loss	1.0000
1:92482861:TA:T	donor_loss	1.0000
1:92482862:ACCTG:A	donor_loss	1.0000
1:92483043:CTGT:C	acceptor_gain	1.0000
1:92476204:TCAC:T	acceptor_gain	0.9900
1:92476205:CACC:C	acceptor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1001017647 (1:92478976 G>A,C,T), RS1001023100 (1:92473725 C>T), RS1001068366 (1:92478538 A>G,T), RS1001142272 (1:92478425 T>C), RS1001193388 (1:92478097 G>C,T), RS1001299200 (1:92479848 GAAAGA>G,GAAAGAAAAGA), RS1001726064 (1:92485098 A>G), RS1002188789 (1:92474400 C>T), RS1002761988 (1:92484261 C>G,T), RS1002776036 (1:92486256 G>T), RS1002899289 (1:92486920 T>G), RS1003024644 (1:92482092 C>T), RS1003078535 (1:92481812 A>G), RS1003173626 (1:92488856 T>C), RS1003237787 (1:92486082 C>A,G)

Disease associations

OMIM: gene MIM:600871 | disease phenotypes: MIM:613107, MIM:607847, MIM:105650, MIM:300908

GenCC curated gene-disease

Disease	Classification	Inheritance
neutropenia, severe congenital, 2, autosomal dominant	Strong	Autosomal dominant
severe congenital neutropenia	Moderate	Autosomal dominant
autosomal dominant severe congenital neutropenia	Supportive	Autosomal dominant

Mondo (6): neutropenia, severe congenital, 2, autosomal dominant (MONDO:0013139), nonimmune chronic idiopathic neutropenia of adults (MONDO:0011922), Diamond-Blackfan anemia (MONDO:0015253), anemia, nonspherocytic hemolytic, due to G6PD deficiency (MONDO:0010480), severe congenital neutropenia (MONDO:0018542), autosomal dominant severe congenital neutropenia (MONDO:0008742)

Orphanet (4): Autosomal dominant severe congenital neutropenia (Orphanet:486), Adult idiopathic neutropenia (Orphanet:2688), Diamond-Blackfan anemia (Orphanet:124), Class I glucose-6-phosphate dehydrogenase deficiency (Orphanet:466026)

HPO phenotypes

33 total (30 of 33 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000155	Oral ulcer
HP:0000230	Gingivitis
HP:0000704	Periodontitis
HP:0000938	Osteopenia
HP:0001028	Hemangioma
HP:0001581	Recurrent skin infections
HP:0001875	Decreased total neutrophil count
HP:0001880	Increased total eosinophil count
HP:0001888	Decreased total lymphocyte count
HP:0001909	Leukemia
HP:0001915	Aplastic anemia
HP:0001945	Fever
HP:0002014	Diarrhea
HP:0002027	Abdominal pain
HP:0002090	Pneumonia
HP:0002718	Recurrent bacterial infections
HP:0002863	Myelodysplasia
HP:0003453	Antineutrophil antibody positivity
HP:0004429	Recurrent viral infections
HP:0004798	Recurrent infection of the gastrointestinal tract
HP:0004808	Acute myeloid leukemia
HP:0005425	Recurrent sinopulmonary infections
HP:0006480	Premature loss of teeth
HP:0006721	Acute lymphoblastic leukemia
HP:0010976	Decreased total B cell count
HP:0011107	Recurrent aphthous stomatitis
HP:0012311	Increased total monocyte count
HP:0012384	Rhinitis
HP:0025439	Pharyngitis

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST005752_181	Systemic lupus erythematosus	1.000000e-07
GCST007120_1	Multiple sclerosis and type 2 diabetes (pleiotropy)	3.000000e-10
GCST007400_6	Systemic lupus erythematosus	5.000000e-07
GCST007563_13	Allergic disease (asthma, hay fever or eczema)	7.000000e-09
GCST009597_48	Multiple sclerosis	1.000000e-14
GCST011346_4	Total cholesterol levels	2.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004574	total cholesterol measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D029503	Anemia, Diamond-Blackfan	C15.378.050.085.080.090; C15.378.050.750.500; C15.378.190.223.500.500.090; C16.320.077.090
C567533	Anemia, Nonspherocytic Hemolytic, Due To G6pd Deficiency (supp.)
C564320	Neutropenia, Nonimmune Chronic Idiopathic, Adult (supp.)
C567748	Neutropenia, Severe Congenital, Autosomal Dominant 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725198 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

36 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, affects expression, affects methylation	4
Arsenic	affects methylation, increases abundance, increases expression	2
Nickel	increases expression	2
Tretinoin	decreases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
GSK-J4	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
baicalein	affects expression, decreases reaction	1
tris(2-butoxyethyl) phosphate	affects expression	1
sodium arsenite	increases abundance, increases expression	1
butyraldehyde	increases expression	1
tobacco tar	increases expression, decreases reaction	1
diallyl disulfide	decreases reaction, increases expression	1
beta-glycerophosphoric acid	affects cotreatment, increases expression, affects reaction	1
pentanal	increases expression	1
pomalidomide	increases expression	1
licochalcone B	decreases expression	1
Decitabine	affects cotreatment, affects expression	1
Vorinostat	affects cotreatment, affects expression	1
Acetaminophen	increases expression	1
Aldehydes	increases expression	1
Ascorbic Acid	affects cotreatment, increases expression, affects reaction	1
Benzene	increases expression	1
Cotinine	affects methylation	1
Dexamethasone	affects cotreatment, increases expression, affects reaction	1
Estradiol	increases expression	1
Methotrexate	decreases expression	1
Progesterone	increases expression, increases reaction	1
Tetradecanoylphorbol Acetate	decreases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697313	Binding	Inhibition of GFI1 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Clinical trials (associated diseases)

43 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01859637	PHASE4	TERMINATED	Immunogenicity, Safety, and Efficacy of Zarzio®/Filgrastim HEXAL® in Patients With Severe Chronic Neutropenia
NCT00673608	PHASE4	COMPLETED	Magnetic Resonance Imaging (MRI) Assessments of the Heart and Liver Iron Load in Patients With Transfusion Induced Iron Overload
NCT00235391	PHASE3	COMPLETED	Expanded Access of Deferasirox to Patients With Congenital Disorders of Red Blood Cells and Chronic Iron Overload
NCT00301834	PHASE2	COMPLETED	Alemtuzumab, Fludarabine, and Busulfan Followed By Donor Stem Cell Transplant in Treating Young Patients With Hematologic Disorders
NCT00909584	PHASE2	TERMINATED	Study of Ezatiostat (Telintra Tablets) for Treatment of Severe Chronic Neutropenia
NCT01529827	PHASE2	COMPLETED	Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT04844177	PHASE2	UNKNOWN	Total Lymphoid Irradiation Pre-HSCT in Severe Congenital Neutropenia
NCT00001962	PHASE2	TERMINATED	A Study to Determine Whether Therapy With Daclizumab Will Benefit Patients With Bone Marrow Failure
NCT00011505	PHASE2	COMPLETED	Mobilization of Stem Cells With G-CSF for Collection From Patients With Diamond-Blackfan Anemia
NCT00957931	PHASE2	COMPLETED	Allo-HCT MUD for Non-malignant Red Blood Cell (RBC) Disorders: Sickle Cell, Thal, and DBA: Reduced Intensity Conditioning, Co-tx MSCs
NCT02386267	PHASE2	UNKNOWN	L-leucine in Diamond Blackfan Anemia Patients
NCT02512679	PHASE2	TERMINATED	Related Hematopoietic Stem Cell Transplantation (HSCT) for Genetic Diseases of Blood Cells
NCT03333486	PHASE2	TERMINATED	Fludarabine Phosphate, Cyclophosphamide, Total Body Irradiation, and Donor Stem Cell Transplant in Treating Patients With Blood Cancer
NCT04099966	PHASE2	RECRUITING	AlloSCT for Malignant and Non-malignant Hematologic Diseases Utilizing Alpha/Beta T Cell and CD19+ B Cell Depletion
NCT04965597	PHASE2	COMPLETED	Treosulfan-Based Conditioning Regimen Before a Blood or Bone Marrow Transplant for the Treatment of Bone Marrow Failure Diseases (BMT CTN 1904)
NCT00295971	PHASE1	COMPLETED	Donor Stem Cell Transplant in Treating Young Patients With Myelodysplastic Syndrome, Leukemia, Bone Marrow Failure Syndrome, or Severe Immunodeficiency Disease
NCT01917708	PHASE1	COMPLETED	Bone Marrow Transplant With Abatacept for Non-Malignant Diseases
NCT01586455	PHASE1	COMPLETED	Human Placental-Derived Stem Cell Transplantation
NCT00176852	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant for Hemoglobinopathy
NCT00305708	PHASE1/PHASE2	COMPLETED	Busulfan, Antithymocyte Globulin, and Fludarabine Followed By a Donor Stem Cell Transplant in Treating Young Patients With Blood Disorders, Bone Marrow Disorders, Chronic Myelogenous Leukemia in First Chronic Phase, or Acute Myeloid Leukemia in First Remission
NCT01852370	PHASE1/PHASE2	ENROLLING_BY_INVITATION	Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases
NCT01966367	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	CD34+ (Non-Malignant) Stem Cell Selection for Patients Receiving Allogeneic Stem Cell Transplantation
NCT01319851	Not specified	TERMINATED	Alefacept and Allogeneic Hematopoietic Stem Cell Transplantation
NCT02179359	Not specified	TERMINATED	Hematopoietic Stem Cell Transplant for High Risk Hemoglobinopathies
NCT02720679	Not specified	RECRUITING	Investigation of the Genetics of Hematologic Diseases
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT00176878	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant for Bone Marrow Failure Syndromes
NCT01362595	PHASE1/PHASE2	COMPLETED	Pilot Phase I/II Study of Amino Acid Leucine in Treatment of Patients With Transfusion-Dependent Diamond Blackfan Anemia
NCT01419704	PHASE1/PHASE2	WITHDRAWN	Phase I/II Pilot Study of Mixed Chimerism to Treat Hemoglobinopathies
NCT01464164	PHASE1/PHASE2	TERMINATED	Safety and Efficacy Study of Sotatercept in Adults With Transfusion Dependent Diamond Blackfan Anemia
NCT02065869	PHASE1/PHASE2	TERMINATED	Safety Study of Gene Modified Donor T-cells Following TCRαβ+ Depleted Stem Cell Transplant
NCT03513328	PHASE1/PHASE2	COMPLETED	Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation
NCT03653338	PHASE1/PHASE2	RECRUITING	T-Cell Depleted Alternative Donor Bone Marrow Transplant for Sickle Cell Disease (SCD) and Other Anemias
NCT03733249	PHASE1/PHASE2	TERMINATED	Long Term Follow-up Study for Patients Enrolled on the BP-004 Clinical Study
NCT03966053	PHASE1/PHASE2	TERMINATED	The Use of Trifluoperazine in Transfusion Dependent DBA
NCT00027274	Not specified	RECRUITING	Cancer in Inherited Bone Marrow Failure Syndromes
NCT00244010	Not specified	COMPLETED	Partially Matched Stem Cell Transplantation for Patients With Refractory Severe Aplastic Anemia or Refractory Cytopenias
NCT00290628	Not specified	TERMINATED	Donor Umbilical Cord Blood Transplant in Treating Patients With Hematologic Cancer
NCT01114776	Not specified	COMPLETED	Multi-Center Study of Iron Overload: Pilot Study
NCT01758042	Not specified	COMPLETED	Bone Marrow and Kidney Transplant for Patients With Chronic Kidney Disease and Blood Disorders