Analyses of caspase-1-regulated transcriptomes in various tissues lead to identification of novel IL-1β-, IL-18- and sirtuin-1-independent pathways.
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.
Centers 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.|Cardiovascular Research, & Thrombosis Research, Departments of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.|The Shanxi Provincial People's Hospital, an Affiliate Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030001, China.
Ya-Feng
YF
Li
Centers 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.
Gayani
G
Nanayakkara
Centers 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.
Yu
Y
Sun
Centers 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.
Xinyuan
X
Li
Centers 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.
Luqiao
L
Wang
Centers 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.
Ramon
R
Cueto
Centers 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.
Ying
Y
Shao
Centers 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.
Hangfei
H
Fu
Centers 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.
Candice
C
Johnson
Centers 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.
Jiali
J
Cheng
Cardiovascular Research, & Thrombosis Research, Departments of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.|Department of Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.
Xiongwen
X
Chen
Centers 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.
Wenhui
W
Hu
Centers 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.|Department of Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.
Jun
J
Yu
Centers 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.|Department of Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.
Eric T
ET
Choi
Centers 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.|Department of Physiology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.
Hong
H
Wang
Centers 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. xfyang@temple.edu.|Cardiovascular Research, & Thrombosis Research, Departments of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA. xfyang@temple.edu.|Department of Physiology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA. xfyang@temple.edu.|Department of Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA. xfyang@temple.edu.
Xiao-Feng
0000-0002-6854-6195
XF
Yang
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism; D020170:Caspase 1 / Q000502:physiology*; D066264:Datasets as Topic; D004734:Energy Metabolism / Q000235:genetics; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics; D020382:Interleukin-18; D053583:Interleukin-1beta; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D000074085:Mice, Knockout, ApoE; D009928:Organ Specificity; D015398:Signal Transduction; D056564:Sirtuin 1; D046888:Tissue Array Analysis; D059467:Transcriptome
D020382:Interleukin-18; D053583:Interleukin-1beta; D020170:Caspase 1; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
Caspase-1; Inflammation and transcriptome; Meta-analysis; Microarray datasets