Analyses of caspase-1-regulated transcriptomes in various tissues lead to identification of novel IL-1β-, IL-18- and sirtuin-1-independent pathways
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Published on: November 27, 2016
Ya-Feng Li1,2,3, Gayani Nanayakkara1, Yu Sun1
1Centers for Metabolic Disease Research and Cardiovascular Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.
Background:
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.
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-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.
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.
Insights
Caspase-1 influences gene expression tissue-specifically, partly independent of known targets like IL-1β, IL-18, and Sirt-1. This suggests caspase-1 regulates novel pathways through unidentified mechanisms.
Area of Science:
- Molecular Biology
- Genomics
- Immunology
Background:
- Caspase-1 is known to regulate IL-1β, IL-18, and Sirt-1.
- Microarray data shows caspase-1 impacts the transcriptome.
- The extent to which caspase-1's transcriptome effects are independent of its known targets remains unclear.
Purpose of the Study:
- To investigate novel global and tissue-specific gene regulatory effects of caspase-1.
- To explore whether caspase-1's transcriptome regulation is independent of IL-1β, IL-18, and Sirt-1.
Main Methods:
- Utilized novel microarray data analysis approaches: Venn analysis, cooperation analysis, and meta-analysis.
- Integrated diverse microarray datasets from caspase-1 knockout tissues.
- Analyzed datasets where caspase-1 downstream targets were manipulated.
Main Results:
- Caspase-1 exhibits tissue-specific gene regulation for most genes.
- Partial cooperation between caspase-1 and Sirt-1 pathways in adipose tissue during injury/inflammation.
- Caspase-1 cooperates with IL-1β in regulating genes related to cardiovascular disease, injury, and cancer in mouse liver.
- Identified 40 globally regulated genes by caspase-1 across tissues, indicating regulation of novel pathways.
- Discovered new cooperatively and non-cooperatively regulated genes within caspase-1, IL-1β, IL-18, and Sirt-1 pathways.
Conclusions:
- Caspase-1 regulates numerous novel signaling pathways.
- These pathways are regulated potentially through known substrates and yet-to-be-identified transcription factors or proteins.
