Krüppel-like factor 4 (KLF4; gut-enriched Krüppel-like factor or GKLF) is a member of the KLF family of zinc finger transcription factors, which belongs to the relatively large family of SP1-like transcription factors. KLF4 is involved in the regulation of proliferation, differentiation, apoptosis and somatic cell reprogramming. Evidence also suggests that KLF4 is a tumor suppressor in certain cancers, including colorectal cancer. It has three Cys₂His₂-zinc fingers at its carboxyl terminus that are closely related to another KLF, KLF2. It has two nuclear localization sequences that signals it to localize to the nucleus. In embryonic stem cells (ESCs), KLF4 has been demonstrated to be a good indicator of stem-like capacity. It is suggested that the same is true in mesenchymal stem cells.

In humans, the protein is 513 amino acids, with a predicted molecular weight of approximately 55kDa, and is encoded by the KLF4 gene. The KLF4 gene is conserved in chimpanzee, rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, and frog. KLF4 was first identified in 1996.

KLF4 can activate transcription by interacting via it N-terminus with specific transcriptional co-activators, such as p300-CBP coactivator family. Transcriptional repression by KLF4 is carried out by KLF4 competing with an activator for binding to a target DNA sequence (9-12). KLF4 has been shown to interact with CREB-binding protein. Furthermore, KLF4 has also been documented to play a role in long range chromatin interactions across the genome. KLF4 has been shown to play a role in methylation of chromatin thus contributing to higher order architectural changes across the genome. Specifically, KLF4 has been shown to bind to methylated gene motifs causing switching from repressive to active chromatin markers, and causing downstream enhanced transcription of KLF4 gene targets. KLF4 has also been documented to interact with protein arginine methyltransferase 1 (Prmt1), which is involved in post translational modifications in regards to cell fate decisions via methylation of histones. It has been shown that KLF4 is methylated by Prmt1 and the methylation of KLF4 by Prmt1 prevents the emergence of primitive endoderm progenitor cells, thus showing the role in which KLF4 interactions play with cell development.

KLF4 has diverse functions, and has been garnering attention in recent years because some of its functions are apparently contradicting, but mainly since the discovery of its integral role as one of four key factors that are essential for inducing pluripotent stem cells. KLF4 is highly expressed in non-dividing cells and its overexpression induces cell cycle arrest. KLF4 is particularly important in preventing cell division when the DNA is damaged. KLF4 is also important in regulating centrosome number and chromosome number (genetic stability), and in promoting cell survival. However, some studies have revealed that under certain conditions KLF4 may switch its role from pro-cell survival to pro-cell death.

KLF4 is expressed in the cells that are non-dividing and are terminally differentiated in the intestinal epithelium, where KLF4 is important in the regulation of intestinal epithelium homeostasis (terminal cell differentiation and proper localization of the different intestinal epithelium cell types). In the intestinal epithelium, KLF4 is an important regulator of Wnt signaling pathway genes of genes regulating differentiation.

KLF4 is expressed in a variety of tissues and organs such as: the cornea where it is required for epithelial barrier function and is a regulator of genes required for corneal homeostasis; the skin where it is required for the development of skin permeability barrier function; the bone and teeth tissues where it regulates normal skeletal development; epithelial cell of the mouse male and female reproductive tract where in the males it is important for proper spermatogenesis; vascular endothelial cells where it is critical in preventing vascular leakage in response to inflammatory stimuli; white blood cells where it mediates inflammatory responses cellular differentiation and proliferation; the kidneys where it is involved in the differentiation of embryonic stem cells and induced pluripotent stem (iPS) cells to renal lineage in vitro and its dysregulation has been linked to some renal pathologies.

Several lines of evidence have shown that KLF4 role in disease is context dependent where under certain conditions it may play one role and under different conditions it may assume a complete opposite role.

KLF4 is an anti-tumorigenic factor and its expression is often lost in various human cancer types, such as Colorectal cancer, gastric cancer, esophageal squamous cell carcinoma, intestinal cancer, prostate cancer, bladder cancer and lung cancer.