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FLASH GENE
Symbol KLF1 contributors: mct/pgu - updated : 09-06-2017
HGNC name Kruppel-like factor 1 (erythroid)
HGNC id 6345
Corresponding disease
CDAN4 congenital dyserythropoietic anemia, 4
Location 19p13.13      Physical location : 12.995.238 - 12.998.017
Synonym name erythroid krueppel-like transcription factor
Synonym symbol(s) EKLF
DNA
TYPE functioning gene
STRUCTURE 2.78 kb     3 Exon(s)
10 Kb 5' upstream gene genomic sequence study
MAPPING cloned Y linked N status confirmed
Physical map
LOC388510 19 LOC388510 LOC90576 19p13.2 hypothetical protein LOC90576 ZNF443 19p13.13 zinc finger protein 443 FLJ38281 19p13.2 hypothetical protein FLJ38281 MGC26914 19p13.2 hypothetical protein MGC26914 PGK1P2 6p21-p12 phosphoglycerate kinase 1, pseudogene 2 ZNF490 19p13.2 zinc finger protein 490 FLJ90396 19p13.2 hypothetical protein FLJ90396 MGC4238 19p13.2 hypothetical protein MGC4238 LOC284393 19p13.2 similar to 60S ribosomal protein L10 (QM protein homolog) MAN2B1 19p13.2-p13.1 mannosidase, alpha, class 2B, member 1 PTD008 19p13.2 PTD008 protein DHPS 19p13.12-p13.11 deoxyhypusine synthase MGC10870 19p13.2 hypothetical protein MGC10870 TNPO2 19p13.2 transportin 2 (importin 3, karyopherin beta 2b) MGC2803 19p13.2 hypothetical protein MGC2803 ASNA1 19q13.3 arsA arsenite transporter, ATP-binding, homolog 1 (bacterial) VMD2L1 19p13.2-p13.12 arsA arsenite transporter, ATP-binding, homolog 1 (bacterial) HOOK2 19p13.2 arsA arsenite transporter, ATP-binding, homolog 1 (bacterial) RNASEH2A 19p13.2 ribonuclease H2, large subunit JUNB 19p13.2 jun B proto-oncogene PRDX2 13q12 peroxiredoxin 2 RTBDN 19p12 retbindin DNASE2 19p13.2 deoxyribonuclease II, lysosomal KLF1 19p13.13-p13.12 Kruppel-like factor 1 (erythroid) GCDH 19p13.2 glutaryl-Coenzyme A dehydrogenase FARSLA 19p13.2 phenylalanine-tRNA synthetase-like, alpha subunit CALR 19p13.3-p13.2 calreticulin RAD23A 19p13.2 RAD23 homolog A (S. cerevisiae) PLINP-1 19p13.2 papillomavirus L2 interacting nuclear protein 1 FLJ38607 19p13.2 hypothetical protein FLJ38607 LOC339375 19p13.13 hypothetical LOC339375 NFIX 19p13.2 nuclear factor I/X (CCAAT-binding transcription factor) LYL1 19p13.2-p13.1 lymphoblastic leukemia derived sequence 1 FLJ20244 19p13.13 hypothetical protein FLJ20244 BTBD14B 19p13.13 BTB (POZ) domain containing 14B STX10 19p13.2 syntaxin 10 ETR101 LOC390891 19 similar to 60S RIBOSOMAL PROTEIN L12 CACNA1A 19p13.2-13.1 calcium channel, voltage-dependent, P/Q type, alpha 1A subunit
RNA
TRANSCRIPTS type messenger
identificationnb exonstypebpproduct
ProteinkDaAAspecific expressionYearPubmed
3 - 1615 - 362 - 1998 9737959
EXPRESSION
Type restricted
   expressed in (based on citations)
organ(s)
tissue
SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
Blood / hematopoieticbone marrow    Homo sapiens
cells
SystemCellPubmedSpeciesStageRna symbol
Blood/Hematopoieticerythroid Homo sapiens
cell lineage erythroid specific
cell lines
fluid/secretion blood
at STAGE
physiological period embryo
Text
  • stem cells
  • fetal liver, spleen and bone marrow (
  • PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a highly conserved 81 AA DNA binding domain
  • two transactivation domains EKLFTAD1 (AAs 140) and EKLFTAD2 (AAs 5190), and a domain (AAs 140232) that is sufficient for activation of beta-globin gene expression
  • three zinc finger of the Cys2-His2 type forming the DNA binding domain
  • KLF1 and KLF2 have highly homologous zinc finger DNA-binding domains
  • a nuclear localization signal (NLS) at the C terminus, with three C2H2-type zinc fingers (ZF)
  • HOMOLOGY
    Homologene
    FAMILY
  • krueppel C2H2-type zinc-finger protein family
  • CATEGORY regulatory , transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,nucleus,chromatin/chromosome
    basic FUNCTION
  • red cell-specific transcription factor
  • activating the beta globin synthesis in fetal liver and adult bone marrow
  • directs different modes of tissue-specific transcriptional activation depending on the architecture of its target core promoter
  • hematopoietic-specific transcription factor that is critical for the activation of subset of erythroid genes
  • essential transcription factor for beta-type globin gene switching, and specifically activates transcription of the adult beta-globin gene promoter
  • recruited to the gamma-globin gene promoter as a co-activator and is required for gamma-globin gene induction by short-chain fatty acid derivatives
  • master regulator of adult beta-globin gene expression, and is also implicated in erythroid processes other than beta-globin gene regulation, such as cell maturation and cell membrane integrity
  • restricts megakaryocytic differentiation to the benefit of erythrocytic differentiation and suggest that this might be at least partially mediated by the inhibition of FLI1 recruitment to megakaryocytic and FLI1 gene promoters
  • likely in coordination with other transcription factors, directly contributes to the complex set of events that occur at the final erythroid cell divisions and accentuates terminal differentiation directly by activation of CDK inhibitors such as CDKN1A
  • erythroid transcription factor, that plays a critical role in the expression of globin genes, but also in the expression of a wide spectrum of genes potentially essential for erythropoiesis
  • potentially controls globin gene switching by directly activating beta-globin and indirectly repressing gamma-globin gene expression
  • regulates definitive erythropoiesis of red blood cells by facilitating transcription through high affinity binding to CACCC elements within its erythroid specific target genes including those encoding erythrocyte membrane skeleton (EMS) proteins (
  • plays an important role in erythroid development by stimulating beta-globin gene expression
  • plays essential roles in embryonic and adult erythropoiesis
  • KLF1 and KLF2 positively regulate the embryonic and fetal beta-globin genes through direct promoter binding
  • distinct yet overlapping mechanistic roles for KLF1 and KLF2 in embryonic red blood cells
  • erythroid-specific transcription factor required for the transcription of genes that regulate erythropoiesis
  • KLF1, KLF2, and MYC control a regulatory network essential for embryonic erythropoiesis
  • important role for the KLF1-BCL11A axis in erythroid maturation and developmental regulation of globin expression
  • acts as a direct activator of genes that encode repressors of gamma-globin gene expression, and is a regulator of many components of the cell cycle machinery
  • crucial zinc finger transcription factor, is expressed in the erythro-myeloid progenitors (EMPs), and plays an extrinsic role in erythroid maturation by being expressed in the supportive macrophage of the erythroblastic island and regulating relevant genes important for island integrity within these cells
  • in erythroid cells, expression of KLF1 precedes PGF, and its enforced expression in human erythroid progenitor cells induces PGF mRNA
  • KLF1 and KLF2 coordinately regulate embryonic erythroid precursor maturation through the regulation of multiple homeostasis-associated genes
  • is an erythroid specific transcription factor that binds to regulatory regions of erythroid genes
  • regulates BCL11A, a known repressor of adult gamma-globin expression
  • role of KLF1 in gamma-globin regulation in fetal erythroblasts is complex, with both positive and negative facets
  • transcription factors such as KLF1, along with epigenetic modifiers, play crucial roles in establishing the proper onset and progression of terminal differentiation events in erythropoiesis
  • essential transcription factor that is required for the proper maturation of the erythroid cells
  • CELLULAR PROCESS nucleotide, chromatin organization, remodeling
    nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA binding to the CACCC site of the promoter and the locus control region LCR-HB-NA@ through a remodeling of chromatin involving a complex including SMARCB1, SMARCC1, SMARCC2 and BRG
    RNA
    small molecule
    protein
  • repressing KLF3 (BKLF)
  • associates with both KLF3 promoters (is typically an activator of transcription, whereas KLF3 is a repressor)
  • interacts with TATA binding protein-associated factor 9 (TAF9), which leads to important consequences for expression of adult beta-globin
  • interacting with BCL11A (KLF1 may control BCL11A expression by both direct and indirect mechanisms)
  • activates a diverse set of genes associated with erythropoiesis, including the beta-globin gene (
  • KLF1 and KLF2 bind directly to the promoters of the HBE1 and HBG1, HBG2 genes
  • through EKLFTAD2 binds the N-terminal PH domain of the GTF2H1 and four domains of EP300
  • PPM1B interacts with KLF1 via its PEST1 sequence
  • BCL11A expression is activated by KLF1, leading to HBG1, HBG2 repression
  • DOK2 is able to control KLF1 expression by transcriptional regulation through directly binding to its promoter region
  • KLF1 binds to the FOXM1 gene promoter in blood cells
  • HIRA is not only critical for HBB expression but is also required for activation of the erythropoietic regulators KLF1 and GATA binding protein 1 (GATA1)
  • KLF1 plays a role in facilitating and/or stabilizing GATA1 and TAL1 occupancy in the erythroid genes, contributing to the generation of active chromatin structure such as histone acetylation and chromatin looping
  • PIAS3 is a transcriptional corepressor of KLF1 for at least a subset of its target genes during erythropoiesis
  • is a critical factor that interacts with an essential upstream enhancer element of the KLF1 promoter and exerts a positive effect on KLF1 levels
  • amount of KLF1 expression strongly positively correlates with HBB mRNA and weakly positively correlates with BCL11A mRNA
  • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) CDAN4
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional germinal mutation      
    inactivating mutations is the first demonstration of a blood group phenotype resulting from mutations in a transcription factor (form the molecular basis of the rare blood group In(Lu) phenotype)
    constitutional     --low  
    would relieve gamma-globin gene repression in adult erythroid progenitors
    constitutional germinal mutation      
    KLF1 mutations modulate the phenotype in a cohort of alpha-thalassemia carriers
    constitutional germinal mutation      
    KLF1 gene promoter mutation (KLF1:g.-148G&8201;>&8201;A) is associated with increased HbF level
    Susceptibility
  • to increased fetal hemoglobin (HbF) levels
  • Variant & Polymorphism other KLF1 variations are associated with increased fetal hemoglobin (HbF) levels
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    bloodhemoglobin 
    controlled knockdown of KLF1 in adult erythroid progenitors may provide a method to activate fetal hemoglobin expression in individuals with beta-thalassemia or sickle cell disease
    ANIMAL & CELL MODELS
  • adult Nan/+ mice exhibit lifelong hemolytic anemia with spherocytosis, whereas Nan/Nan embryos die in utero at 12.5 days gestation (