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. [5]
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]
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. [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.
Next-Generation sequencing efforts have revealed a surprisingly high prevalence of mutations in human KLF1. [9] The chance of a KLF1 null child being conceived is approximately 1:24,000 in Southern China. [10] With pre-natal blood transfusions and bone marrow transplant, it is possible to be born without KLF1. [11] Most mutations in KLF1 lead to a recessive loss-of-function phenotype, [10] however semi-dominant mutations have been identified in humans [12] and mice [13] as the cause of a rare inherited anemia CDA type IV. Additional family studies and clinical research [14] unveiled the molecular genetics of the HPFH KLF1-related condition and established KLF1 as a novel quantitative trait locus for HbF (HBFQTL6). [15] Permissive nature of the role of KLF1 on expression of several RBC antigens are evidenced by a series of known KLF1 mutations which are named after its modifier gene effect on Lutheral blood group In(Lu) ie "Inhibitor of Lutheran". No homozygouse alive human examples are known, corroborating with the Embryonic lethality of KLF1 homozygous mice. So the In(Lu) mutatants are significantly heteroinsuffient for KLF1 function such that RBC are formed, but there is an apparent dominant negative effect on expression of Lutheran Antigen (Basal cell adhesion Molecule) after which it was named, but also significant but somewhat variable degree of inhibition of expression of Colton (Aquaporin1), Ok (CD147 ie EMMPRIN), Indian(CD44), Duffy (Duffy antigen/chemokine receptor or Fy), Scianna (ERMAP), MN (glycophorin A), Diego(band 3), P1, i, AnWj (CD44) etc. Antigens on RBC membrane, [16] and some of which might overlap with KLF1 mutations causing the fraction of hereditary persistence of fetal hemoglobin with CDA type IV.
An insulator is a type of cis-regulatory element known as a long-range regulatory element. Found in multicellular eukaryotes and working over distances from the promoter element of the target gene, an insulator is typically 300 bp to 2000 bp in length. Insulators contain clustered binding sites for sequence specific DNA-binding proteins and mediate intra- and inter-chromosomal interactions.
GATA-binding factor 1 or GATA-1 is the founding member of the GATA family of transcription factors. This protein is widely expressed throughout vertebrate species. In humans and mice, it is encoded by the GATA1 and Gata1 genes, respectively. These genes are located on the X chromosome in both species.
In molecular genetics, the Krüppel-like family of transcription factors (KLFs) are a set of eukaryotic C2H2 zinc finger DNA-binding proteins that regulate gene expression. This family has been expanded to also include the Sp transcription factor and related proteins, forming the Sp/KLF family.
The erythropoietin receptor (EpoR) is a protein that in humans is encoded by the EPOR gene. EpoR is a 52 kDa peptide with a single carbohydrate chain resulting in an approximately 56–57 kDa protein found on the surface of EPO responding cells. It is a member of the cytokine receptor family. EpoR pre-exists as dimers. These dimers were originally thought to be formed by extracellular domain interactions, however, it is now assumed that it is formed by interactions of the transmembrane domain and that the original structure of the extracellular interaction site was due to crystallisation conditions and does not depict the native conformation. Binding of a 30 kDa ligand erythropoietin (Epo), changes the receptor's conformational change, resulting in the autophosphorylation of Jak2 kinases that are pre-associated with the receptor. At present, the best-established function of EpoR is to promote proliferation and rescue of erythroid progenitors from apoptosis.
A locus control region (LCR) is a long-range cis-regulatory element that enhances expression of linked genes at distal chromatin sites. It functions in a copy number-dependent manner and is tissue-specific, as seen in the selective expression of β-globin genes in erythroid cells. Expression levels of genes can be modified by the LCR and gene-proximal elements, such as promoters, enhancers, and silencers. The LCR functions by recruiting chromatin-modifying, coactivator, and transcription complexes. Its sequence is conserved in many vertebrates, and conservation of specific sites may suggest importance in function. It has been compared to a super-enhancer as both perform long-range cis regulation via recruitment of the transcription complex.
The human β-globin locus is composed of five genes located on a short region of chromosome 11, responsible for the creation of the beta parts of the oxygen transport protein Haemoglobin. This locus contains not only the beta globin gene but also delta, gamma-A, gamma-G, and epsilon globin. Expression of all of these genes is controlled by single locus control region (LCR), and the genes are differentially expressed throughout development.
PDX1, also known as insulin promoter factor 1, is a transcription factor in the ParaHox gene cluster. In vertebrates, Pdx1 is necessary for pancreatic development, including β-cell maturation, and duodenal differentiation. In humans this protein is encoded by the PDX1 gene, which was formerly known as IPF1. The gene was originally identified in the clawed frog Xenopus laevis and is present widely across the evolutionary diversity of bilaterian animals, although it has been lost in evolution in arthropods and nematodes. Despite the gene name being Pdx1, there is no Pdx2 gene in most animals; single-copy Pdx1 orthologs have been identified in all mammals. Coelacanth and cartilaginous fish are, so far, the only vertebrates shown to have two Pdx genes, Pdx1 and Pdx2.
GATA2 or GATA-binding factor 2 is a transcription factor, i.e. a nuclear protein which regulates the expression of genes. It regulates many genes that are critical for the embryonic development, self-renewal, maintenance, and functionality of blood-forming, lympathic system-forming, and other tissue-forming stem cells. GATA2 is encoded by the GATA2 gene, a gene which often suffers germline and somatic mutations which lead to a wide range of familial and sporadic diseases, respectively. The gene and its product are targets for the treatment of these diseases.
Krüppel-like Factor 2 (KLF2), also known as lung Krüppel-like Factor (LKLF), is a protein that in humans is encoded by the KLF2 gene on chromosome 19. It is in the Krüppel-like factor family of zinc finger transcription factors, and it has been implicated in a variety of biochemical processes in the human body, including lung development, embryonic erythropoiesis, epithelial integrity, T-cell viability, and adipogenesis.
Alpha-globin transcription factor CP2 is a protein that in humans is encoded by the TFCP2 gene.
Transcription factor NF-E2 45 kDa subunit is a protein that in humans is encoded by the NFE2 gene.
Kruppel-like factor 13, also known as KLF13, is a protein that in humans is encoded by the KLF13 gene.
Transcription factor MafK is a bZip Maf transcription factor protein that in humans is encoded by the MAFK gene.
Krueppel-like factor 8 is a protein that in humans is encoded by the KLF8 gene. KLF8 belongs to the family of KLF protein. KLF8 is activated by KLF1 along with KLF3 while KLF3 represses KLF8.
Hemoglobin subunit theta-1 is a protein that in humans is encoded by the HBQ1 gene.
Krüppel-like factor 3 is a protein that in humans is encoded by the KLF3 gene.
B-cell CLL/lymphoma 9 protein is a protein that in humans is encoded by the BCL9 gene.
Nuclear factor -like factor 3, also known as NFE2L3 or 'NRF3', is a transcription factor that in humans is encoded by the Nfe2l3 gene.
Forkhead box protein A2 (FOXA2), also known as hepatocyte nuclear factor 3-beta (HNF-3B), is a transcription factor that plays an important role during development, in mature tissues and, when dysregulated or mutated, also in cancer.
Chromatin target of PRMT1 is a protein that in humans is encoded by the CHTOP gene.
