Abstract
Despite increasing evidence to indicate that long non-coding RNAs (lncRNAs) are novel regulators of immunity, there has been no systematic attempt to identify and characterize the lncRNAs whose expression is changed following the induction of the innate immune response. To address this issue, we have employed next-generation sequencing data to determine the changes in the lncRNA profile in four human (monocytes, macrophages, epithelium, and chondrocytes) and four mouse cell types (RAW 264.7 macrophages, bone marrow-derived macrophages, peritoneal macrophages, and splenic dendritic cells) following exposure to the pro-inflammatory mediators, lipopolysaccharides (LPS), or interleukin-1β. We show differential expression of 204 human and 210 mouse lncRNAs, with positional analysis demonstrating correlation with immune-related genes. These lncRNAs are predominantly cell-type specific, composed of large regions of repeat sequences, and show poor evolutionary conservation. Comparison within the human and mouse sequences showed less than 1% sequence conservation, although we identified multiple conserved motifs. Of the 204 human lncRNAs, 21 overlapped with syntenic mouse lncRNAs, of which five were differentially expressed in both species. Among these syntenic lncRNA was IL7-AS (antisense), which was induced in multiple cell types and shown to regulate the production of the pro-inflammatory mediator interleukin-6 in both human and mouse cells. In summary, we have identified and characterized those lncRNAs that are differentially expressed following activation of the human and mouse innate immune responses and believe that these catalogs will provide the foundation for the future analysis of the role of lncRNAs in immune and inflammatory responses.
Highlights
High-throughput sequencing indicates that much of the human genome is transcribed into non-coding RNAs with estimates of the proportion varying from ~62% predicted by the ENCODE project [1] to ~10% based on evolutionary conservation [2]
Using next-generation sequencing data from four human and four mouse cell types, we have undertaken the first comprehensive analysis of the changes in long non-coding RNA (lncRNA) expression associated with the activation of the innate immune response
This is important since differential expression has commonly provided the initial step in the search for functional lncRNAs and has led to the identification a number that regulate the associated inflammatory response including PACER [13], THRIL [14], lncIL7R [15], and IL1β-RBT46 [16] in humans and long intergenic non-coding RNA (lincRNA)-COX2 [17, 18], lincRNA-EPS [19], and lincRNA-Tnfaip3 [20] in mice
Summary
High-throughput sequencing indicates that much of the human genome is transcribed into non-coding RNAs (ncRNAs) with estimates of the proportion varying from ~62% predicted by the ENCODE project [1] to ~10% based on evolutionary conservation [2]. LncRNAs are classified by their relative position to protein-coding mRNAs and include the long intergenic ncRNAs (lincRNAs), antisense (AS), and pseudogenes [8]. The identification of these domains has been hindered by their poor evolutionary conservation, which, in contrast to protein-coding genes, does not require the maintenance of a conserved open reading frame for optimal translation [6]. It is thought that the lncRNAs conservation is geared toward the maintenance of genomic position (synteny), short domains (microdomains), and secondary structure [7, 10]
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