Krüppel-like factors in mammalian stem cells and development

Abstract

Krüppel-like factors (KLFs) are a family of zinc-finger transcription factors that are found in many species. Recent studies have shown that KLFs play a fundamental role in regulating diverse biological processes such as cell proliferation, differentiation, development and regeneration. Of note, several KLFs are also crucial for maintaining pluripotency and, hence, have been linked to reprogramming and regenerative medicine approaches. Here, we review the crucial functions of KLFs in mammalian embryogenesis, stem cell biology and regeneration, as revealed by studies of animal models. We also highlight how KLFs have been implicated in human diseases and outline potential avenues for future research.

Keywords: Cellular regeneration; Human disease; Krüppel-like factors; Mammalian development; Stem cells.

Fig. 1.

Schematic of the domain structure of human KLF proteins. All KLFs possess three highly conserved C2H2 zinc finger domains in their carboxyl-terminal regions that mediate transcriptional activation and/or repression. By contrast, their N-terminal regions are less conserved, harboring additional motifs, such as CtBP-motifs and Cabut domains/SID-binding motifs, that are implicated in protein-protein and protein-DNA interactions. Some KLFs also contain nuclear localization signals (NLSs) and nuclear export signals (NESs) that regulate their subcellular localization. Proteins are drawn to scale.

Fig. 2.

Phylogenetic relationship between human and mouse KLF family members. An amino acid alignment was produced from full-length mouse and human KLF family members using MAFFT (Katoh et al., 2002) employing the L-INS-i algorithm and BLOSUM45 scoring matrix. As KLF family members share little homology outside of the C-terminal ZNF region, the alignment was trimmed 22 residues N-terminal of the first ZNF domain and one residue C-terminal of the third ZNF domain. Phylogenetic analysis of the ZNF region was performed via RAxML 7.2.8 (Stamatakis, 2006) using the Gamma LG model, and node support in the ML tree was sampled via 100 bootstrap replicates. Both alignment and phylogenetic analyses were performed in Geneious version 8.1.8 (Kearse et al., 2012). Scale bar: 0.2 amino acid changes per site.

Fig. 3.

The expression of KLF2, KLF4 and KLF5 during mammalian pre-implantation embryo development. Diagram of mouse pre-implantation embryo development, highlighting the stages at which KLF2, KLF4 and KLF5 genes are expressed; the expression of these factors in human pre-implantation embryos is also indicated. Patterns of expression are based on findings reported by Blakeley et al. (2015) and Lin et al. (2010). EPI, epiblast; ICM, inner cell mass; PE, primitive ectoderm; TE, trophectoderm.

Fig. 4.

KLFs and pluripotency. Schematic summarizing some of the regulatory interactions between KLF2, KLF4, KLF5 and factors involved in pluripotency in iPSCs. Interactions are based on findings reported by Jiang et al. (2008) and Hall et al. (2009). Arrows indicate induction of expression, with the thickness of arrows indicating the level of induction.

Fig. 5.

Summary of the roles of KLFs in human disease. Diagram summarizing the specific roles reported for KLFs in neuronal disorders, cardiovascular diseases, kidney diseases, gastrointestinal disorders and hematopoietic disorders. It should be noted that the involvement of KLFs in various types of cancer is not included in this schematic.