zinc finger protein Gfi-1; growth factor independent protein 1; zinc finger protein 163 (GFI1, ZNF163)

Function

• transcription repressor essential for hematopoiesis
• functions in a cell-context & 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
  • EHMT2-GFI1-HDAC1
  • AJUBA-GFI1-HDAC1
  • RCOR-GFI-KDM1A-HDAC
• these complexes suppress, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development
• regulates neutrophil differentiation, promotes proliferation of lymphoid cells, & is required for granulocyte development
• mediates, together with U2AF1L4, the alternative splicing of CD45 & controls T-cell receptor signaling
• regulates the endotoxin- mediated Toll-like receptor 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 promoter
• required for maintenance of inner ear hair cells
• ubiquitinated
• ubiquitination & degradation by the proteasome is inhibited by the ubiquitin ligase, ARIH2
• interacts with U2AF1L4
• component of RCOR-GFI-KDM1A-HDAC complexes
  • interacts directly with RCOR1, KDM1A & HDAC2
  • also interacts with HDAC1
• interacts (via the Zn+2-finger domain) with ARIH2
  • the interaction prevents GFI1 ubiquitination & proteasomal degradation
• interacts with PIAS3
• the interaction relieves the inhibitory effect of PIAS3 on STAT3-mediated transcriptional activity
• forms a complex with EHMT2 & HDAC1 to promote Lys-9 dimethylation of H3 (H3K9Me2) & 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 &, occurs independently of the SNAG domain
• interacts with SPI1
  • the interaction inhibits SPI1 transcriptional activity & represses SPI1-regulated macrophage-specific genes required for proper granulocyte development
• interacts with RUNX1T1;
  • the interaction represses HDAC-mediated transcriptional activity
• interacts with RELA; the interaction occurs on liposaccharide (LPS) stimulation & controls RELA DNA binding activity & regulates endotoxin-mediated TOLL-like receptor inflammatory response
• interacts (via the C-terminal Zn+2 fingers) with ZBTB17
  • the interaction results in the recruitment of GFI1 to the CDKN1A/p21 promoter & repression of CDKN1A/p21 transcription

Structure

• C2H2-type Zn+2 fingers 3, 4 & 5 are required for DNA-binding & for interaction with SPI1
• the SNAG domain of GFIs is required for nuclear location & for interaction with some corepressors (putative)
• contains 6 C2H2-type Zn+2 fingers

Compartment

• nucleus
• colocalizes with PIAS3 & RUNX1T1 in nuclear dots

Expression

down-regulated by TGFB1

Pathology

• defects in GFI1 are a cause of
  • neutropenia severe congenital autosomal dominant type 2 b)dominant nonimmune chronic idiopathic neutropenia of adults

More general terms

• C2H2 type zinc finger protein
• transcriptional silencer (transcriptional repressor)
• phosphoprotein

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=2672
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:2672
• OMIM: https://mirror.omim.org/entry/600871
• OMIM: https://mirror.omim.org/entry/607847
• OMIM: https://mirror.omim.org/entry/613107
• UniProt: http://www.uniprot.org/uniprot/Q99684.html