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.
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.[1]
Function
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.[2]
Over-expression of KLF1 results in a reduction of the number of circulating platelets and hastens the onset of the β-globin gene.[3]
KLF1 coordinates the regulation of six cellular pathways that are all essential to terminal erythroid differentiation:[4]
Cell Membrane & Cytoskeleton
Apoptosis
Heme Synthesis & Transport
Cell Cycling
Iron Procurement
Globin Chain Production
It has also been linked to three main processes that are all essential to transcription of the β globin gene:
KLF1 binds specifically to the "CACCC" motif of the β-globin gene promoter.[2] 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
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.[5] With pre-natal blood transfusions and bone marrow transplant, it is possible to be born without KLF1.[6] Most mutations in KLF1 lead to a recessive loss-of-function phenotype,[5] however semi-dominant mutations have been identified in humans[7] and mice[8] as the cause of a rare inherited anemia CDA type IV.
↑ 2.02.1Perkins, Andrew; Sharpe, Ariene; Orkin, Stuart (1995). "Lethal β-thalassaemia in mice lacking the erythroid CACCC-transcription factor EKLF". Nature. 375 (6529): 318–322. doi:10.1038/375318a0. PMID7753195.
↑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. doi:10.1093/emboj/17.8.2334. PMID9545245.
↑Tallack, Michael; Perkins, Andrew (2010). "KLF1 Directly Coordinates Almost All Aspects of Terminal Erythroid Differentiation". IUBMB Life. 62 (12): 886–890. doi:10.1002/iub.404. PMID21190291.
↑ 5.05.1Perkins, 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. doi:10.1182/blood-2016-01-694331. PMID26903544.
↑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.
↑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. doi:10.1093/nar/gkw1014. PMID27899603.
External links
Cooley's Anemia Foundation. About Thalassemia [Internet]. New York, NY: Cooley's Anemia Foundation National Office; 2001 [1 August 2007] . Available from: http://cooleysanemia.org/sections.php?sec=1&tab=8