Analyses of caspase-1-regulated transcriptomes in various tissues lead to identification of novel IL-1β-, IL-18- and sirtuin-1-independent pathways

Ya-feng Li, Gayani Nanayakkara, Yu Sun, Xinyuan Li, Luqiao Wang, Ramon Cueto, Ying Shao, Hangfei Fu, Candice Johnson, Jiali Cheng, Xiongwen Chen, Wenhui Hu, Jun Yu, Eric T. Choi, Hong Wang, Xiao-feng Yang

It is well established that caspase-1 exerts its biological activities through its downstream targets such as IL-1β, IL-18, and Sirt-1. The microarray datasets derived from various caspase-1 knockout tissues indicated that caspase-1 can significantly impact the transcriptome. However, it is not known whether all the effects exerted by caspase-1 on transcriptome are mediated only by its well-known substrates. Therefore, we hypothesized that the effects of caspase-1 on transcriptome may be partially independent from IL-1β, IL-18, and Sirt-1. To determine new global and tissue-specific gene regulatory effects of caspase-1, we took novel microarray data analysis approaches including Venn analysis, cooperation analysis, and meta-analysis methods. We used these statistical methods to integrate different microarray datasets conducted on different caspase-1 knockout tissues and datasets where caspase-1 downstream targets were manipulated. We made the following important findings: (1) Caspase-1 exerts its regulatory effects on the majority of genes in a tissue-specific manner; (2) Caspase-1 regulatory genes partially cooperates with genes regulated by sirtuin-1 during organ injury and inflammation in adipose tissue but not in the liver; (3) Caspase-1 cooperates with IL-1β in regulating less than half of the genes involved in cardiovascular disease, organismal injury, and cancer in mouse liver; (4) The meta-analysis identifies 40 caspase-1 globally regulated genes across tissues, suggesting that caspase-1 globally regulates many novel pathways; and (5) The meta-analysis identified new cooperatively and non-cooperatively regulated genes in caspase-1, IL-1β, IL-18, and Sirt-1 pathways. Our findings suggest that caspase-1 regulates many new signaling pathways potentially via its known substrates and also via transcription factors and other proteins that are yet to be identified.