KLFs

Kruppel-like factors (KLFs) are a family of transcription factors that regulate gene expression during development and in adult tissues. In vertebrates, the family comprises multiple genes, each encoding a protein with a conserved DNA-binding domain and variable regulatory regions that determine context-specific activity.

A defining feature of KLFs is a conserved C-terminal region containing three C2H2 zinc-finger motifs, which bind GC-rich DNA elements such as CACCC boxes and related GC boxes found in promoters and enhancers. The N-terminal portions of KLF proteins are diverse and can function as transcriptional activators or repressors, often in association with cofactors that modulate their activity and specificity.

KLFs play roles in numerous biological processes, including cell proliferation, differentiation, metabolism, and apoptosis. Specific family members have well-characterized functions in particular tissues: KLF1 is essential for erythroid maturation and regulation of hemoglobin genes; KLF2 contributes to vascular and immune cell homeostasis; KLF4 is involved in epithelial barrier function and can promote or inhibit pluripotency depending on context; KLF5 influences proliferation and differentiation in several lineages; KLF6 has been described as a tumor suppressor in some settings. The family also includes members with deeper or more context-dependent roles in development and disease.

Regulation of KLF activity occurs at multiple levels, including transcriptional control, post-transcriptional regulation, and post-translational modifications such as phosphorylation. Signaling pathways such as MAPK and PI3K/Akt can affect DNA binding and transcriptional output, and interactions with coactivators or corepressors further shape their effects on target genes.

Clinically, altered KLF function has been linked to cancer, cardiovascular and metabolic disorders, and inflammatory diseases. KLF proteins are studied as potential therapeutic targets and, in some cases, as tools for cellular reprogramming, as exemplified by the use of KLF4 in induced pluripotent stem cell generation. The KLF family is evolutionarily conserved and expanded through gene duplication, yielding a network of factors with overlapping and distinct roles.