Transcription factors Krüppel-like factor 4 and paired box 5 regulate the expression of the Grainyhead-like genes

Abstract

Genes from the Grainyhead-like (GRHL) family code for transcription factors necessary for the development and maintenance of various epithelia. These genes are also very important in the development of many types of cancer. However, little is known about the regulation of expression of GRHL genes. Previously, there were no systematic analyses of the promoters of GRHL genes or transcription factors that bind to these promoters. Here we report that the Krüppel-like factor 4 (KLF4) and the paired box 5 factor (PAX5) bind to the regulatory regions of the GRHL genes and regulate their expression. Ectopic expression of KLF4 or PAX5 alters the expression of GRHL genes. In KLF4-overexpressing HEK293 cells, the expression of GRHL1 and GRHL3 genes was upregulated by 32% and 60%, respectively, whereas the mRNA level of GRHL2 gene was lowered by 28% when compared to the respective controls. The levels of GRHL1 and GRHL3 expression were decreased by 30% or 33% in PAX5-overexpressing HEK293 cells. The presence of minor frequency allele of single nucleotide polymorphism rs115898376 in the promoter of the GRHL1 gene affected the binding of KLF4 to this site. The evidence presented here suggests an important role of KLF4 and PAX5 in the regulation of expression of GRHL1-3 genes.

Loss-of-function variants in KLF4 underlie autosomal dominant palmoplantar keratoderma

“…33 Interestingly, TP63 ablation negatively affects DSG1 expression. 34 Furthermore, although we showed that KLF4 directly regulates DSG1, KLF4 loss-of function variants may also affect DSG1 expression indirectly because KLF4 was shown to transactivate the GRHL1 gene that encodes GRHL1, 35 and GRHL1 null mice have reduced DSG1 expression and develop PPK. 36 The mild phenotype displayed by patients harboring pathogenic KLF4 variants, a nonpainful form of PPK, contrasts with the multifaceted role of KLF4, 20 which has been shown in various mouse models to be critical for the development of a wide range of tissues, including epidermis, cornea, and gut epithelia.…”