Kruppel-like factors

Family of zinc finger transcription factors
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 proliferation of KLF genes, presumably from an ancestral KLF, is also interesting. In some cases different family members are expressed in different tissues. The first KLF, KLF1, originally known as Erythroid KLF (EKLF) is expressed only in red blood cells and megakaryocytes. It drives red blood cell differentiation and represses megakaryocyte formation. It appears that it has arisen as a KLF family member that has a particular role in these two blood lineages. Other KLFs are more broadly expressed and there are interactions between family members. KLF3 for instance is driven by KLF1 as is KLF8. On the other hand, KLF3 represses KLF8. Such cross regulation occurs extensively in transcription factor families. Many transcription factor genes regulate their own promoters and when a gene duplicates during evolution then cross regulation often occurs. The cross regulation can ensure that the total amount of KLFs in the cell is monitored and controlled. Finally, the biological roles of the KLFs are of wide interest. KLF1 is a very important factor in red blood cell biology. Naturally occurring human mutations in the KLF1 gene have been associated with de repression of the fetal globin gene. KLF2 (originally Lung KLF ) also has a role in embryonic globin gene expression, as does KLF3 (originally Basic KLF). KLF3 also has roles in adipocyte or fat formation, and in B lymphocytes. Recently, KLF3 was shown to be important in heart development. KLF4 (originally Gut KLF) is an important gene in the gut and skin but has more recently risen to prominence as one of the four genes that can reprogram body cells to become stem cells. [KLF4] is one of the so called magic four transcription factors, KLF4, Oct4, Sox2 and Myc. KLF5, like KLF3, is important in adipocytes and KLF6 is an important tumour suppressor gene, that is often mutated in prostate cancers.

KLF3 has a short motif in the N terminus (of the form Proline Isoleucine Aspartate Leucine Serine or PIDLS) that recruits CtBP1 and 2. CtBP in turn recruits histone modifying enzymes. It brings in histone deacetylases, histone demethylases and histone methylases, which are thought to
remove active chromatin marks and lay down repressive marks to eliminate gene expression.

<! Deleted image removed: [[File:KLF4props2. png|thumb|KLF4 protein domains. Transcriptional activation domain (AD), transcriptional inhibitory domain (ID), zinc finger DNA binding domain, nuclear localization signal (NLS) and potential PEST sequence. Several point mutations have been identified in tumor cells, which are shown in blue. Redrawn after Wei et al.

Little is known of the Klfs in the myocardium. Klf5 activates the promoter of the hypertrophic agonist platelet derived growth factor (PDGFA) in cardiac fibroblasts a factor previously identified as being upregulated by ET 1, and Klf5+/ transgenic mice heterozygotes (described earlier) exhibited less cardiac fibrosis and hypertrophy when stimulated with angiotensin II compared with controls. Klf5 is itself regulated by the immediate early gene egr 1 in VSMCs, which, if similarly regulated in the cardiomyocyte, places Klf5 potentially in a position to co ordinate the acute response to external stress and tissue remodelling in the myocardium.

The understanding of the structure and function of KLFs has informed the design of artificial transcription factors. Artificial zinc fingers can be built to recognize chosen sites in DNA and artificial functional domains can be added to either activate or repress genes containing these sites.