Insights into the Function of Long Noncoding RNAs in Sepsis Revealed by Gene Co-Expression Network Analysis

Sepsis is a major cause of death and its incidence and mortality increase exponentially with age. Most gene expression studies in sepsis have focused in protein-coding genes and the expression patterns, and potential roles of long noncoding RNAs (lncRNAs) have not been investigated yet.

Here, researchers from the Universidade de São Paulo performed co-expression network analysis of protein-coding and lncRNAs measured in neutrophil granulocytes from adult and elderly septic patients, along with age-matched healthy controls. They found that the genes displaying highest network similarity are predominantly differently expressed in sepsis and are enriched in loci encoding proteins with structural or regulatory functions related to protein translation and mitochondrial energetic metabolism. A number of lncRNAs are strongly connected to genes from these pathways and may take part in regulatory loops that are perturbed in sepsis. Among those, the ribosomal pseudogenes RP11-302F12.1 and RPL13AP7 are differentially expressed and appear to have a regulatory role on protein translation in both the elderly and adults, and lncRNAs MALAT1, LINC00355, MYCNOS, and AC010970.2 display variable connection strength and inverted expression patterns between adult and elderly networks, suggesting that they are the best candidates to be further studied to understand the mechanisms by which the immune response is impaired by age.

Unsupervised hierarchical clustering of samples from sepsis (“se” for elderly and “sa” for adults) and healthy controls (“ce” for elderly and “ca” for adults) based on long noncoding RNA (lncRNA) expression. Expression measurements from the top 5% more variable lncRNAs (based on their coefficient of variation across all samples) were used to group samples using UPGMA clustering and Pearson correlation as a distance measurement. Samples are labeled according to disease status (sepsis in red, healthy controls in blue) and age (elderly subjects are shown in darker colors whereas those from young adults are shown in lighter colors).

The researchers report the expression of lncRNAs that are deregulated in patients with sepsis, including subsets that display hub properties in molecular pathways relevant to the disease pathogenesis and that may participate in gene expression regulatory circuits related to the poorer disease outcome observed in elderly subjects.