Krueppel-like factor 1 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that in humans is encoded by the KLF1

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

. The gene for KLF1 is on the human chromosome 19 and on mouse chromosome 8. Krueppel-like factor 1 is a

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...

that is necessary for the proper maturation of

erythroid Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "hol ...

(red blood) cells.

Structure

The molecule has two domains; the

transactivation domain The transactivation domain or trans-activating domain (TAD) is a transcription factor scaffold domain which contains binding sites for other proteins such as transcription coregulators. These binding sites are frequently referred to as activation ...

and the

chromatin Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in r ...

-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 Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out ...

# Modulation of the gamma to

beta globin Hemoglobin subunit beta (beta globin, β-globin, haemoglobin beta, hemoglobin beta) is a globin protein, coded for by the ''HBB'' gene, which along with alpha globin ( HBA), makes up the most common form of haemoglobin in adult humans, hemoglobi ...

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 Thalassemias are inherited blood disorders characterized by decreased hemoglobin production. Symptoms depend on the type and can vary from none to severe. Often there is mild to severe anemia (low red blood cells or hemoglobin). Anemia can result ...

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. Additional family studies and clinical research unveiled the molecular genetics of the HPFH KLF1-related condition and established KLF1 as a novel quantitative trait locus for HbF (HBFQTL6). 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". Interestingly 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, and some of which might overlap with KLF1 mutations causing the fraction of hereditary persistence of fetal hemoglobin with CDA type IV.

References

External links

* {{Use dmy dates, date=April 2017 Transcription factors