Species Human Entrez 10661 | Human Mouse Ensembl ENSG00000105610 | |
Aliases KLF1, CDAN4, EKLF, HBFQTL6, INLU, Kruppel-like factor 1 (erythroid), Kruppel like factor 1 External IDs MGI: 1342771 HomoloGene: 4785 GeneCards: KLF1 | ||
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.
Contents
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.
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. Over-expression of KLF1 results in a reduction of the number of circulating platelets and hastens the onset of the β-globin gene.
KLF1 coordinates the regulation of six cellular pathways that are all essential to terminal erythroid differentiation:
- 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. 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. With pre-natal blood transfusions and bone marrow transplant, it is possible to be born without KLF1. Most mutations in KLF1 lead to a recessive loss-of-function phenotype, however semi-dominant mutations have been identified in humans and mice as the cause of a rare inherited anemia CDA type IV.