Wang Tao, Li Jinge, Ding Ke, Zhang Li, Che Qiuru, Sun Xiuming, Dai Yumeng, Sun Wei, Bao Meiying, Wang Xiaochun, Yang Liquan, Li Zhiwei
The Center for Combinatorial Chemistry and Drug Discovery, School of Pharmaceutical Science, Jilin University, Changchun 130012, China.
Int J Mol Sci. 2017 Mar 1;18(3):528. doi: 10.3390/ijms18030528.
NF-κB is an important transcription factor that plays critical roles in cell survival, proliferation, inflammation, and cancers. Although the majority of experimentally identified functional NF-κB binding sites (κB sites) match the consensus sequence, there are plenty of non-functional NF-κB consensus sequences in the genome. We analyzed the surrounding sequences of the known κB sites that perfectly match the GGGRNNYYCC consensus sequence and identified the nucleotide at the -1 position of κB sites as a key contributor to the binding of the κB sites by NF-κB. We demonstrated that a cytosine at the -1 position of a κB site (-1C) could be methylated, which thereafter impaired NF-κB binding and/or function. In addition, all -1C κB sites are located in CpG islands and are conserved during evolution only when they are within CpG islands. Interestingly, when there are multiple NF-κB binding possibilities, methylation of -1C might increase NF-κB binding. Our finding suggests that a single nucleotide at the -1 position of a κB site could be a critical factor in NF-κB functioning and could be exploited as an additional manner to regulate the expression of NF-κB target genes.
核因子-κB（NF-κB）是一种重要的转录因子，在细胞存活、增殖、炎症和癌症中发挥关键作用。尽管大多数通过实验确定的功能性NF-κB结合位点（κB位点）与共有序列匹配，但基因组中存在大量非功能性的NF-κB共有序列。我们分析了已知κB位点的侧翼序列，这些位点与GGGRNNYYCC共有序列完美匹配，并确定κB位点-1位置的核苷酸是NF-κB与κB位点结合的关键因素。我们证明，κB位点-1位置的胞嘧啶（-1C）可以被甲基化，进而损害NF-κB的结合和/或功能。此外，所有-1C κB位点都位于CpG岛中，并且仅当它们位于CpG岛内时在进化过程中才保守。有趣的是，当存在多种NF-κB结合可能性时，-1C的甲基化可能会增加NF-κB的结合。我们的发现表明，κB位点-1位置的单个核苷酸可能是NF-κB功能的关键因素，并且可以作为调节NF-κB靶基因表达的另一种方式加以利用。
