Faculty of Biology, Institute of Genetics and Biotechnology, University of Warsaw, Warsaw, Poland.
Laboratory of Bioinformatics, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland.
PLoS One. 2021 Sep 27;16(9):e0257977. doi: 10.1371/journal.pone.0257977. eCollection 2021.
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.
GRHL 样家族的基因编码转录因子，对于各种上皮组织的发育和维持是必需的。这些基因在多种癌症的发展中也非常重要。然而，关于 GRHL 基因表达的调控知之甚少。以前，没有对 GRHL 基因的启动子或与这些启动子结合的转录因子进行系统分析。在这里，我们报告 Krüppel 样因子 4（KLF4）和配对盒 5 因子（PAX5）结合到 GRHL 基因的调控区域并调节其表达。KLF4 或 PAX5 的异位表达改变了 GRHL 基因的表达。在 KLF4 过表达的 HEK293 细胞中，GRHL1 和 GRHL3 基因的表达分别上调了 32%和 60%，而 GRHL2 基因的 mRNA 水平与各自的对照相比降低了 28%。在 PAX5 过表达的 HEK293 细胞中，GRHL1 和 GRHL3 的表达水平分别降低了 30%或 33%。GRHL1 基因启动子中单核苷酸多态性 rs115898376 的次要频率等位基因的存在影响了 KLF4 与该位点的结合。这里提供的证据表明 KLF4 和 PAX5 在调节 GRHL1-3 基因表达中起着重要作用。
