Alternative titles; symbols
HGNC Approved Gene Symbol: KLF3
Cytogenetic location: 4p14 Genomic coordinates (GRCh38): 4:38,664,199-38,701,517 (from NCBI)
Kruppel-like transcription factors, such as KLF3, are characterized by 3 highly conserved C-terminal C2H2 zinc finger domains that bind CACCC boxes and other GC-rich regions in DNA. KLF3 functions primarily as a transcriptional repressor through recruitment of the corepressor C-terminal binding protein (see CTBP2; 602619) and associated chromatin-modifying enzymes (summary by Funnell et al., 2012).
In their review, Turner and Crossley (1999) stated that KLF3, or BKLF, contains a DNA-binding region that consists of 3 zinc finger domains near its C terminus and a patch of conserved basic residues immediately upstream of the zinc fingers. The N terminus of BKLF contains a large number of basic residues. Mouse Bklf protein is expressed in many cell types, including hematopoietic cells and fibroblasts, and is present at high levels in brain.
Suske et al. (2005) stated that the human and mouse KLF3 proteins contain 345 and 344 amino acids, respectively. Both have a characteristic zinc finger domain, but lack the N-terminal buttonhead box found in related SP transcription factors.
Suske et al. (2005) stated that the human KLF3 gene maps to chromosome 4p14, and the mouse Klf3 gene maps to chromosome 5C3.3.
In their review, Turner and Crossley (1999) stated that BKLF binds CACCC/CGCCC motifs through its DNA-binding region and functions as a transcriptional repressor in hematopoietic cells. Mouse Bklf interacts with Ctbp2, a cofactor that associates with other hematopoietic transcriptional repressors.
Sue et al. (2008) found that Klf3 -/- mice were born at less than the expected mendelian ratio. Klf3 -/- mice were indistinguishable from Klf3 +/- and wildtype mice, but by weaning they were visibly smaller with lower body weight. Low body weight was due to reduced white adipose tissue caused by fewer and smaller sized cells in fat pads of Klf3 -/- mice. In culture, Klf3 -/- mouse embryonic fibroblasts (MEFs) showed enhanced adipocyte differentiation and enhanced ability to accumulate lipid compared with wildtype cells. Further analysis with 3T3-L1 cell culture and Klf3 -/- cells demonstrated that Klf3 and its corepressor, Ctbp, regulated adipocyte differentiation by repressing expression of Cebpa (116897) by binding to the CACCC motif in its promoter.
Funnell et al. (2012) found that Klf3 -/- mice had mild compensated anemia with erythroid defects in spleen and bone marrow. Fetal liver of Klf3 -/- mice showed reduced erythroid cell maturation. Klf3 expression increased during erythroid cell maturation, and Klf3 repressed gene transcription at later stages of erythroid maturation. Some genes repressed by Klf3 overlapped with a subset of genes regulated by Eklf (KLF1; 600599). Klf3 repressed Eklf activity at some CACCC-dependent targets, thereby helping to refine the functional subset of Eklf-inducible genes during erythroid maturation.
Funnell et al. (2013) found that Klf8 (300286) -/- males and females were viable and fertile, but that they had a significantly shortened lifespan compared with wildtype. Klf3 -/- mice were viable, but they were essentially infertile. Knockout of both Klf3 and Klf8 resulted in embryonic lethality, suggesting genetic interaction between the 2 genes. RT-PCR analysis showed that Klf8 expression was upregulated in Klf3 -/- erythroid tissues. Microarray assays revealed that fetal liver of Klf3 -/- Klf8 -/- embryos exhibited greater dysregulation of gene expression than either single mutant, particularly derepression of embryonic, but not adult, globin expression. Klf3 repressed expression of embryonic globin genes in erythroid cells, and Klf8 partially compensated in its absence.
Funnell, A. P. W., Mak, K. S., Twine, N. A., Pelka, G. J., Norton, L. J., Radziewic, T., Power, M., Wilkins, M. R., Bell-Anderson, K. S., Fraser, S. T., Perkins, A. C., Tam, P. P., Pearson, R. C. M., Crossley, M. Generation of mice deficient in both KLF3/BKLF and KLF8 reveals a genetic interaction and a role for these factors in embryonic globin gene silencing. Molec. Cell. Biol. 33: 2976-2987, 2013. [PubMed: 23716600] [Full Text: https://doi.org/10.1128/MCB.00074-13]
Funnell, A. P. W., Norton, L. J., Mak, K. S., Burdach, J., Artuz, C. M., Twine, N. A., Wilkins, M. R., Power, C. A., Hung, T.-T., Perdomo, J., Koh, P., Bell-Anderson, K. S., Orkin, S. H., Fraser, S. T., Perkins, A. C., Pearson, R. C. M., Crossley, M. The CACCC-binding protein KLF3/BKLF suppresses a subset of KLF1/EKLF target genes and is required for proper erythroid maturation in vivo. Molec. Cell. Biol. 32: 3281-3292, 2012. [PubMed: 22711990] [Full Text: https://doi.org/10.1128/MCB.00173-12]
Sue, N., Jack, B. H. A., Eaton, S. A., Pearson, R. C. M., Funnell, A. P. W., Turner, J., Czolij, R., Denyer, G., Bao, S., Molero-Navajas, J. C., Perkins, A., Fujiwara, Y., Orkin, S. H., Bell-Anderson, K., Crossley, M. Targeted disruption of the basic Kruppel-like factor gene (Klf3) reveals a role in adipogenesis. Molec. Cell. Biol. 28: 3967-3978, 2008. [PubMed: 18391014] [Full Text: https://doi.org/10.1128/MCB.01942-07]
Suske, G., Bruford, E., Philipsen, S. Mammalian SP/KLF transcription factors: bring in the family. Genomics 85: 551-556, 2005. [PubMed: 15820306] [Full Text: https://doi.org/10.1016/j.ygeno.2005.01.005]
Turner, J., Crossley, M. Basic Kruppel-like factor functions within a network of interacting haematopoietic transcription factors. Int. J. Biochem. Cell Biol. 31: 1169-1174, 1999. [PubMed: 10582345] [Full Text: https://doi.org/10.1016/s1357-2725(99)00067-9]