KLF1

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KLF1
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases KLF1, CDAN4, EKLF, HBFQTL6, INLU, Kruppel-like factor 1 (erythroid), Kruppel like factor 1
External IDs MGI: 1342771 HomoloGene: 4785 GeneCards: KLF1
Gene location (Human)
Chromosome 19 (human)
Chr. Chromosome 19 (human)[1]
Chromosome 19 (human)
Genomic location for KLF1
Genomic location for KLF1
Band No data available Start 12,884,423 bp[1]
End 12,887,181 bp[1]
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_006563

NM_010635

RefSeq (protein)

NP_006554

NP_034765

Location (UCSC) Chr 19: 12.88 – 12.89 Mb Chr 19: 84.9 – 84.91 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Krueppel-like factor 1 is a protein that in humans is encoded by the KLF1 gene. The gene for KLF1 is on the human chromosome 19 and on mouse chromosome 8. Krueppel-like factor 1 is a transcription factor that is necessary for the proper maturation of erythroid (red blood) cells.

Structure[edit]

The molecule has two domains; the transactivation domain and the chromatin-remodeling domain. The carboxyl (C) terminal is composed of three C2H2 zinc fingers that binds to DNA, and the amino (N) terminus is proline rich and acidic.[5]

Function[edit]

Studies in mice first demonstrated the critical function of KLF1 in hematopoietic development. KLF1 deficient (knockout) mouse embryos exhibit a lethal anemic phenotype, fail to promote the transcription of adult β-globin, and die by embryonic day 15.[6] Over-expression of KLF1 results in a reduction of the number of circulating platelets and hastens the onset of the β-globin gene.[7]

KLF1 coordinates the regulation of six cellular pathways that are all essential to terminal erythroid differentiation:[8]

  1. Cell Membrane & Cytoskeleton
  2. Apoptosis
  3. Heme Synthesis & Transport
  4. Cell Cycling
  5. Iron Procurement
  6. Globin Chain Production

It has also been linked to three main processes that are all essential to transcription of the β globin gene:

  1. Chromatin remodeling
  2. Modulation of the gamma to beta globin switch
  3. Transcriptional activation

KLF1 binds specifically to the "CACCC" motif of the β-globin gene promoter.[6] When natural mutations occur in the promoter, β+ thalassemia can arise in humans. Thalassemia's prevalence (2 million worldwide carry the trait) makes KLF1 clinically significant.

Clinical significance[edit]

Next-Generation sequencing efforts have revealed a surprisingly high prevalence of mutations in human KLF1. The chance of a KLF1 null child being conceived is approximately 1:24,000 in Southern China.[9] With pre-natal blood transfusions and bone marrow transplant, it is possible to be born without KLF1.[10] Most mutations in KLF1 lead to a recessive loss-of-function phenotype,[9] however semi-dominant mutations have been identified in humans[11] and mice[12] as the cause of a rare inherited anemia CDA type IV.

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000105610 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000054191 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". 
  4. ^ "Mouse PubMed Reference:". 
  5. ^ Brown RC, Pattison S, van Ree J, Coghill E, Perkins A, Jane SM, Cunningham JM (January 2002). "Distinct domains of erythroid Krüppel-like factor modulate chromatin remodeling and transactivation at the endogenous beta-globin gene promoter". Mol. Cell. Biol. 22 (1): 161–70. PMC 134232Freely accessible. PMID 11739731. doi:10.1128/mcb.22.1.161-170.2002. 
  6. ^ a b Perkins, Andrew; Sharpe, Ariene; Orkin, Stuart (1995). "Lethal β-thalassaemia in mice lacking the erythroid CACCC-transcription factor EKLF.". Nature. 375 (6529): 318–322. PMID 7753195. doi:10.1038/375318a0. 
  7. ^ Tewari, Rita; Gillemans, Nynke; Wijgerde, Mark; Nuez, Beatriz; von Lindern, Marieke; Grosveld, Frank; Philipsen, Sjaak (1998). "Erythroid Krüppel-like factor (EKLF) is active in primitive and definitive erythroid cells and is required for the function of 5 HS3 of the β-globin locus control region". EMBO J. 17 (8): 2334–2341. PMID 9545245. doi:10.1093/emboj/17.8.2334. 
  8. ^ Tallack, Michael; Perkins, Andrew (2010). "KLF1 Directly Coordinates Almost All Aspects of Terminal Erythroid Differentiation". IUBMB Life. 62 (12): 886–890. PMID 21190291. doi:10.1002/iub.404. 
  9. ^ a b Perkins, Andrew; Xu, Xiangmin; Higgs, Douglas; The KLF1 Consensus Workgroup; Patrinos, George; Arnaud, Lionel; Bieker, James; Philipsen, Sjaak (2016). "Krüppeling erythropoiesis: an unexpected broad spectrum of human red blood cell disorders due to KLF1 variants.". Blood. 127 (15): 1856–1862. PMID 26903544. doi:10.1182/blood-2016-01-694331. 
  10. ^ Magor, Graham; Tallack, Michael; Gillinder, Kevin; Bell, Charles; McCallum, Naomi; Williams, Bronwyn; Perkins, Andrew (2014). "KLF1-null neonates display hydrops fetalis and a deranged erythroid transcriptome". Blood. 125 (15): 2405–2417. PMID 25724378. doi:10.1182/blood-2014-08-590968. 
  11. ^ Arnaud, Lionel; Saison, Carole; Helias, Virginie; Lucien, Nicole; Steschenko, Dominique; Giarratana, Marie-Catherine; Prehu, Claude; Foliguet, Bernard; Montout, Lory; de Brevern, Alexandre G.; Francina, Alain; Ripoche, Pierre; Fenneteau, Odile; Da Costa, Lydie; Peyrard, Thierry; Coghlan, Gail; Illum, Niels; Birgens, Henrik; Tamary, Hannah; Iolascon, Achille; Delaunay, Jean; Tchernia, Gil; Cartron, Jean-Pierre (2010). "A Dominant Mutation in the Gene Encoding the Erythroid Transcription Factor KLF1 Causes a Congenital Dyserythropoietic Anemia". The American Journal of Human Genetics. 87 (5): 721–727. doi:10.1016/j.ajhg.2010.10.010. 
  12. ^ Gillinder, KR; Ilsley, MD; Nébor, D; Sachidanandam, R; Lajoie, M; Magor, GW; Tallack, MR; Bailey, T; Landsberg, MJ; Mackay, JP; Parker, MW; Miles, LA; Graber, JH; Peters, LL; Bieker, JJ; Perkins, AC (2016). "Promiscuous DNA-binding of a mutant zinc finger protein corrupts the transcriptome and diminishes cell viability.". Nucleic acids research. PMID 27899603. doi:10.1093/nar/gkw1014. 

External links[edit]