KLF1: Difference between revisions
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== Structure == | == Structure == | ||
The molecule has two domains; the [[Transcription factor#Trans-activating domain|transactivation domain]] and the [[chromatin]]-remodeling domain. The carboxyl (C) terminal is composed of three C2H2 [[zinc finger]]s that binds to DNA, and the amino (N) terminus is proline rich and acidic.<ref name="pmid11739731">{{cite journal |vauthors=Brown RC, Pattison S, van Ree J, Coghill E, Perkins A, Jane SM, Cunningham JM | title = Distinct domains of erythroid Krüppel-like factor modulate chromatin remodeling and transactivation at the endogenous beta-globin gene promoter | journal = | The molecule has two domains; the [[Transcription factor#Trans-activating domain|transactivation domain]] and the [[chromatin]]-remodeling domain. The carboxyl (C) terminal is composed of three C2H2 [[zinc finger]]s that binds to DNA, and the amino (N) terminus is proline rich and acidic.<ref name="pmid11739731">{{cite journal | vauthors = Brown RC, Pattison S, van Ree J, Coghill E, Perkins A, Jane SM, Cunningham JM | title = Distinct domains of erythroid Krüppel-like factor modulate chromatin remodeling and transactivation at the endogenous beta-globin gene promoter | journal = Molecular and Cellular Biology | volume = 22 | issue = 1 | pages = 161–70 | date = January 2002 | pmid = 11739731 | pmc = 134232 | doi = 10.1128/mcb.22.1.161-170.2002 }}</ref> | ||
== Function == | == 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.<ref name="Perkins et al">{{cite journal| | 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.<ref name="Perkins et al">{{cite journal | vauthors = Perkins AC, Sharpe AH, Orkin SH | title = Lethal beta-thalassaemia in mice lacking the erythroid CACCC-transcription factor EKLF | journal = Nature | volume = 375 | issue = 6529 | pages = 318–22 | date = May 1995 | pmid = 7753195 | doi = 10.1038/375318a0 }}</ref> | ||
Over-expression of KLF1 results in a reduction of the number of circulating platelets and hastens the onset of the β-globin gene.<ref>{{cite journal| | Over-expression of KLF1 results in a reduction of the number of circulating platelets and hastens the onset of the β-globin gene.<ref>{{cite journal | vauthors = Tewari R, Gillemans N, Wijgerde M, Nuez B, von Lindern M, Grosveld F, Philipsen S | title = Erythroid Krüppel-like factor (EKLF) is active in primitive and definitive erythroid cells and is required for the function of 5'HS3 of the beta-globin locus control region | journal = The EMBO Journal | volume = 17 | issue = 8 | pages = 2334–41 | date = April 1998 | pmid = 9545245 | pmc = 1170576 | doi = 10.1093/emboj/17.8.2334 }}</ref> | ||
KLF1 coordinates the regulation of six cellular pathways that are all essential to terminal erythroid differentiation:<ref>{{cite journal| | KLF1 coordinates the regulation of six cellular pathways that are all essential to terminal erythroid differentiation:<ref>{{cite journal | vauthors = Tallack MR, Perkins AC | title = KLF1 directly coordinates almost all aspects of terminal erythroid differentiation | journal = IUBMB Life | volume = 62 | issue = 12 | pages = 886–90 | date = December 2010 | pmid = 21190291 | doi = 10.1002/iub.404 }}</ref> | ||
# Cell Membrane & Cytoskeleton | # Cell Membrane & Cytoskeleton | ||
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== Clinical significance == | == 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.<ref name="Perkins review">{{cite journal| | Next-Generation sequencing efforts have revealed a surprisingly high prevalence of mutations in human KLF1.<ref>{{cite journal | vauthors = Gillinder K, Magor G, Perkins A | title = Variable serologic and other phenotypes due to KLF1 mutations | journal = Transfusion | volume = 58 | issue = 5 | pages = 1324–1325 | date = May 2018 | pmid = 29683509 | doi = 10.1111/trf.14529 }}</ref> The chance of a KLF1 null child being conceived is approximately 1:24,000 in Southern China.<ref name="Perkins review">{{cite journal | vauthors = Perkins A, Xu X, Higgs DR, Patrinos GP, Arnaud L, Bieker JJ, Philipsen S | title = Krüppeling erythropoiesis: an unexpected broad spectrum of human red blood cell disorders due to KLF1 variants | journal = Blood | volume = 127 | issue = 15 | pages = 1856–62 | date = April 2016 | pmid = 26903544 | pmc = 4832505 | doi = 10.1182/blood-2016-01-694331 | first8 = Sjaak | first5 = George | first6 = Lionel | first7 = James }}</ref> With pre-natal blood transfusions and bone marrow transplant, it is possible to be born without KLF1.<ref>{{cite journal | vauthors = Magor GW, Tallack MR, Gillinder KR, Bell CC, McCallum N, Williams B, Perkins AC | title = KLF1-null neonates display hydrops fetalis and a deranged erythroid transcriptome | journal = Blood | volume = 125 | issue = 15 | pages = 2405–17 | date = April 2015 | pmid = 25724378 | pmc = 4521397 | doi = 10.1182/blood-2014-08-590968 }}</ref> Most mutations in KLF1 lead to a recessive loss-of-function phenotype,<ref name="Perkins review" /> however semi-dominant mutations have been identified in humans<ref>{{cite journal | vauthors = Arnaud L, Saison C, Helias V, Lucien N, Steschenko D, Giarratana MC, Prehu C, Foliguet B, Montout L, de Brevern AG, Francina A, Ripoche P, Fenneteau O, Da Costa L, Peyrard T, Coghlan G, Illum N, Birgens H, Tamary H, Iolascon A, Delaunay J, Tchernia G, Cartron JP | title = A dominant mutation in the gene encoding the erythroid transcription factor KLF1 causes a congenital dyserythropoietic anemia | journal = American Journal of Human Genetics | volume = 87 | issue = 5 | pages = 721–7 | date = November 2010 | pmid = 21055716 | doi = 10.1016/j.ajhg.2010.10.010 }}</ref> and mice<ref>{{cite journal | vauthors = 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 | title = Promiscuous DNA-binding of a mutant zinc finger protein corrupts the transcriptome and diminishes cell viability | journal = Nucleic Acids Research | volume = 45 | issue = 3 | pages = 1130–1143 | date = February 2017 | pmid = 28180284 | pmc = 5388391 | doi = 10.1093/nar/gkw1014 }}</ref> as the cause of a rare inherited anemia [[Congenital dyserythropoietic anemia|CDA type IV]]. Additional family studies and clinical research<ref>{{cite journal | vauthors = Borg J, Papadopoulos P, Georgitsi M, Gutiérrez L, Grech G, Fanis P, Phylactides M, Verkerk AJ, van der Spek PJ, Scerri CA, Cassar W, Galdies R, van Ijcken W, Ozgür Z, Gillemans N, Hou J, Bugeja M, Grosveld FG, von Lindern M, Felice AE, Patrinos GP, Philipsen S | title = Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin | journal = Nature Genetics | volume = 42 | issue = 9 | pages = 801–5 | date = September 2010 | pmid = 20676099 | pmc = 2930131 | doi = 10.1038/ng.630 }}</ref> unveiled the molecular genetics of the HPFH KLF1-related condition and established KLF1 as a novel quantitative trait locus for HbF (HBFQTL6).<ref>{{OMIM|613566|HBFQTL6}}</ref> | ||
== References== | == References== | ||
{{Reflist}} | {{Reflist}} | ||
{{Transcription factors|g2}} | {{Transcription factors|g2}} | ||
Latest revision as of 15:39, 24 October 2018
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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
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:
- Chromatin remodeling
- Modulation of the gamma to beta globin switch
- Transcriptional activation
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.[5] The chance of a KLF1 null child being conceived is approximately 1:24,000 in Southern China.[6] With pre-natal blood transfusions and bone marrow transplant, it is possible to be born without KLF1.[7] Most mutations in KLF1 lead to a recessive loss-of-function phenotype,[6] however semi-dominant mutations have been identified in humans[8] and mice[9] as the cause of a rare inherited anemia CDA type IV. Additional family studies and clinical research[10] unveiled the molecular genetics of the HPFH KLF1-related condition and established KLF1 as a novel quantitative trait locus for HbF (HBFQTL6).[11]
References
- ↑ 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". Molecular and Cellular Biology. 22 (1): 161–70. doi:10.1128/mcb.22.1.161-170.2002. PMC 134232. PMID 11739731.
- ↑ 2.0 2.1 Perkins AC, Sharpe AH, Orkin SH (May 1995). "Lethal beta-thalassaemia in mice lacking the erythroid CACCC-transcription factor EKLF". Nature. 375 (6529): 318–22. doi:10.1038/375318a0. PMID 7753195.
- ↑ Tewari R, Gillemans N, Wijgerde M, Nuez B, von Lindern M, Grosveld F, Philipsen S (April 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 beta-globin locus control region". The EMBO Journal. 17 (8): 2334–41. doi:10.1093/emboj/17.8.2334. PMC 1170576. PMID 9545245.
- ↑ Tallack MR, Perkins AC (December 2010). "KLF1 directly coordinates almost all aspects of terminal erythroid differentiation". IUBMB Life. 62 (12): 886–90. doi:10.1002/iub.404. PMID 21190291.
- ↑ Gillinder K, Magor G, Perkins A (May 2018). "Variable serologic and other phenotypes due to KLF1 mutations". Transfusion. 58 (5): 1324–1325. doi:10.1111/trf.14529. PMID 29683509.
- ↑ 6.0 6.1 Perkins A, Xu X, Higgs DR, Patrinos GP, Arnaud L, Bieker JJ, Philipsen S (April 2016). "Krüppeling erythropoiesis: an unexpected broad spectrum of human red blood cell disorders due to KLF1 variants". Blood. 127 (15): 1856–62. doi:10.1182/blood-2016-01-694331. PMC 4832505. PMID 26903544.
- ↑ Magor GW, Tallack MR, Gillinder KR, Bell CC, McCallum N, Williams B, Perkins AC (April 2015). "KLF1-null neonates display hydrops fetalis and a deranged erythroid transcriptome". Blood. 125 (15): 2405–17. doi:10.1182/blood-2014-08-590968. PMC 4521397. PMID 25724378.
- ↑ Arnaud L, Saison C, Helias V, Lucien N, Steschenko D, Giarratana MC, Prehu C, Foliguet B, Montout L, de Brevern AG, Francina A, Ripoche P, Fenneteau O, Da Costa L, Peyrard T, Coghlan G, Illum N, Birgens H, Tamary H, Iolascon A, Delaunay J, Tchernia G, Cartron JP (November 2010). "A dominant mutation in the gene encoding the erythroid transcription factor KLF1 causes a congenital dyserythropoietic anemia". American Journal of Human Genetics. 87 (5): 721–7. doi:10.1016/j.ajhg.2010.10.010. PMID 21055716.
- ↑ 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 (February 2017). "Promiscuous DNA-binding of a mutant zinc finger protein corrupts the transcriptome and diminishes cell viability". Nucleic Acids Research. 45 (3): 1130–1143. doi:10.1093/nar/gkw1014. PMC 5388391. PMID 28180284.
- ↑ Borg J, Papadopoulos P, Georgitsi M, Gutiérrez L, Grech G, Fanis P, Phylactides M, Verkerk AJ, van der Spek PJ, Scerri CA, Cassar W, Galdies R, van Ijcken W, Ozgür Z, Gillemans N, Hou J, Bugeja M, Grosveld FG, von Lindern M, Felice AE, Patrinos GP, Philipsen S (September 2010). "Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin". Nature Genetics. 42 (9): 801–5. doi:10.1038/ng.630. PMC 2930131. PMID 20676099.
- ↑ Online Mendelian Inheritance in Man (OMIM) HBFQTL6 -613566