Analyses of caspase-1-regulated transcriptomes in various tissues lead to identification of novel IL-1β-, IL-18- and sirtuin-1-independent pathways.
Analyses of caspase-1-regulated transcriptomes in various tissues lead to identification of novel IL-1β-, IL-18- and sirtuin-1-independent pathways.
复制标题
分析各种组织中 caspase-1- 调节的转录组导致新的 IL-1β-、IL-18- 和 Sirtuin-1 独立途径的鉴定。
DOI：
10.1186/s13045-017-0406-2
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发表时间：
2017-02-02
影响因子：
28.5
通讯作者：
Yang XF
中科院分区：
文献类型：
--
作者：
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
已经确定，半胱天冬酶-1通过其下游靶标如IL-1β、IL-18和Sirt-1发挥其生物活性。来自各种caspase-1敲除组织的微阵列数据集表明caspase-1可以显著影响转录组。然而，目前尚不清楚caspase-1对转录组的所有作用是否仅由其众所周知的底物介导。因此，我们假设caspase-1对转录组的影响可能部分独立于IL-1β、IL-18和Sirt-1。为了确定caspase-1新的全局和组织特异性基因调控作用，我们采用了新的微阵列数据分析方法，包括维恩分析，合作分析和荟萃分析方法。我们使用这些统计方法来整合在不同的caspase-1敲除组织上进行的不同的微阵列数据集和操纵caspase-1下游靶点的数据集。我们的研究结果表明：（1）Caspase-1以组织特异性方式对大多数基因发挥调控作用：（2）在脂肪组织器官损伤和炎症过程中，Caspase-1调控基因与sirtuin-1调控基因部分协同作用，但在肝脏中不协同作用;（3）Caspase-1与IL-1β协同调节不到一半的与小鼠肝脏心血管疾病、有机体损伤和癌症相关的基因;（4）荟萃分析确定了40个caspase-1在组织中全局调节的基因，表明caspase-1全局调节许多新的途径;（5）荟萃分析确定了caspase-1、IL-1β、IL-18和Sirt-1途径中新的协同和非协同调节基因。我们的研究结果表明，caspase-1可能通过其已知的底物，也通过转录因子和其他尚未确定的蛋白质来调节许多新的信号通路。本文的在线版本（doi：10.1186/s13045-017-0406-2）包含补充材料，可供授权用户使用。
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. The online version of this article (doi:10.1186/s13045-017-0406-2) contains supplementary material, which is available to authorized users.