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

• Published in: Journal of hematology and oncology Vol. 10; no. 1; p. 40
• Main Authors: Li, Ya-Feng, Nanayakkara, Gayani, Sun, Yu, Li, Xinyuan, Wang, Luqiao, Cueto, Ramon, Shao, Ying, Fu, Hangfei, Johnson, Candice, Cheng, Jiali, Chen, Xiongwen, Hu, Wenhui, Yu, Jun, Choi, Eric T, Wang, Hong, Yang, Xiao-Feng
• Format: Journal Article
• Language: English
• Published: England BioMed Central 02-02-2017; BMC
• Subjects: Adipose Tissue - metabolism; Animals; Aorta - metabolism; Caspase 1 - physiology; Caspase-1; Datasets as Topic; Energy Metabolism - genetics; Gene Expression Regulation; Inflammation - genetics; Inflammation and transcriptome; Interleukin-18; Interleukin-1beta; Liver - metabolism; Male; Meta-analysis; Mice; Mice, Knockout, ApoE; Microarray datasets; Organ Specificity; Signal Transduction; Sirtuin 1; Tissue Array Analysis; Transcriptome; Inflammation and transcriptome; Microarray datasets; Caspase-1; Meta-analysis
• ISSN: 1756-8722; 1756-8722
• DOI: 10.1186/s13045-017-0406-2

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.