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Li YF , Nanayakkara G , Sun Y , Li X , Wang L , Cueto R , Shao Y , Fu H , Johnson C , Cheng J , Chen X , Hu W , Yu J , Choi ET , Wang H , Yang XF
Analyses of caspase-1-regulated transcriptomes in various tissues lead to identification of novel IL-1beta-, IL-18- and sirtuin-1-independent pathways
J Hematol Oncol. 2017 Feb 2;10(1) :40
PMID: 28153032    PMCID: PMC5290602    URL: https://www.ncbi.nlm.nih.gov/pubmed/28153032
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BACKGROUND: It is well established that caspase-1 exerts its biological activities through its downstream targets such as IL-1beta, 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-1beta, IL-18, and Sirt-1. METHODS: 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. RESULTS: 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-1beta 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-1beta, IL-18, and Sirt-1 pathways. CONCLUSIONS: 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.
1756-8722 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 ORCID: http://orcid.org/0000-0002-6854-6195 R01 HL088243/HL/NHLBI NIH HHS/United States R01 HL132399/HL/NHLBI NIH HHS/United States Journal Article England J Hematol Oncol. 2017 Feb 2;10(1):40. doi: 10.1186/s13045-017-0406-2.