Abstract
BackgroundSepsis is a fatal disease referring to the presence of a known or strongly suspected infection coupled with systemic and uncontrolled immune activation causing multiple organ failure. However, current knowledge of the role of lncRNAs in sepsis is still extremely limited.MethodsWe performed an in silico investigation of the gene coexpression pattern for the patients response to all-cause sepsis in consecutive intensive care unit (ICU) admissions. Sepsis coexpression gene modules were identified using WGCNA and enrichment analysis. lncRNAs were determined as sepsis biomarkers based on the interactions among lncRNAs and the identified modules.ResultsTwenty-three sepsis modules, including both differentially expressed modules and prognostic modules, were identified from the whole blood RNA expression profiling of sepsis patients. Five lncRNAs, FENDRR, MALAT1, TUG1, CRNDE, and ANCR, were detected as sepsis regulators based on the interactions among lncRNAs and the identified coexpression modules. Furthermore, we found that CRNDE and MALAT1 may act as miRNA sponges of sepsis related miRNAs to regulate the expression of sepsis modules. Ultimately, FENDRR, MALAT1, TUG1, and CRNDE were reannotated using three independent lncRNA expression datasets and validated as differentially expressed lncRNAs.ConclusionThe procedure facilitates the identification of prognostic biomarkers and novel therapeutic strategies of sepsis. Our findings highlight the importance of transcriptome modularity and regulatory lncRNAs in the progress of sepsis.
Highlights
Sepsis is a fatal disease referring to the presence of a known or strongly suspected infection coupled with systemic and uncontrolled immune activation causing multiple organ failure
The interactions were established using hypergeometric test to assess whether a sepsis module significantly overrepresents the target genes of a Long non-coding RNAs (lncRNAs). (12) Select the hub lnRNAs connecting more than three sepsis modules as sepsis candidate lncRNAs
FENDRR, the FOXF1 adjacent non-coding developmental regulatory RNA, plays as a hub regulator mediating 14 sepsis modules in the lncRNA-module interaction network. Both MALAT1 and CRNDE regulate ten sepsis modules and we investigated the regulatory mechanism of how the lncRNAs regulate the modules in sepsis from the perspective of competing endogenous RNAs, which impact the translation rate of mRNAs by competing for shared miRNAs [22, 23]. lncRNAs are able to share the same miRNA response elements with mRNAs transferred by the sepsis modules, thereby sponging miRNAs intended to bind to these mRNAs and depressing the overall expression level of sepsis modules (Fig. 5c)
Summary
Sepsis is a fatal disease referring to the presence of a known or strongly suspected infection coupled with systemic and uncontrolled immune activation causing multiple organ failure. Transcriptomic strategies have been adopted among numerous diseases to investigate differential expression analysis, coexpression pattern, survival analysis, prediction modeling, etc., leading to substantial advances in the identification of promising diagnostic biomarkers as well as clinical use and disease treatment [4,5,6] Poll and his colleagues have utilized the highthroughput blood gene expression profiling to carry out the comparative analysis of the systemic response for sepsis patients diagnosed in distinct subgroups and endotypes, such as community-acquired and hospitalacquired pneumonia, bacterial sepsis and fungal sepsis, hyper-inflammatory and hypo-inflammatory, and critically ill patients in different platelet counts [7,8,9,10]. A computational framework was proposed to predict moonlighting lncRNAs by clustering the protein interaction network to determine modules with independent functions [17]
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