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Review
. 2016 Jan 2:212:146-60.
doi: 10.1016/j.virusres.2015.07.003. Epub 2015 Jul 9.

Long non-coding RNAs in innate and adaptive immunity

Thomas M Aune  1 , Charles F Spurlock 3rd  2
Affiliations
Review

Long non-coding RNAs in innate and adaptive immunity

Thomas M Aune et al. Virus Res. .

Abstract

Long noncoding RNAs (lncRNAs) represent a newly discovered class of regulatory molecules that impact a variety of biological processes in cells and organ systems. In humans, it is estimated that there may be more than twice as many lncRNA genes than protein-coding genes. However, only a handful of lncRNAs have been analyzed in detail. In this review, we describe expression and functions of lncRNAs that have been demonstrated to impact innate and adaptive immunity. These emerging paradigms illustrate remarkably diverse mechanisms that lncRNAs utilize to impact the transcriptional programs of immune cells required to fight against pathogens and maintain normal health and homeostasis.

Keywords: Epigenetics; Immune system; Long non-coding RNA; Transcriptional regulation; Whole genome RNA-sequencing.

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Figures

Fig. 1
Fig. 1
Comparison of non-coding and coding genes across different genomes. (A) Venndiagram illustrates numbers and percentages of known genes in human and mouse genomes (adapted from GENCODE, 2015 update). (B) Increased complexity of organisms is associated with marked expansion of genome size and non-coding RNA. X-axis is genome size in bp and Y-axis is size of the genome encoding mRNA or ncRNA (adapted from: Liu, G, Mattick, JS, Taft, RJ. ‘A meta-analysis of the genomic and transcriptomic composition of complex life’. Cell Cycle 12:2061–2072, 2013).
Fig. 2
Fig. 2
Anatomy of long noncoding RNA (lncRNA) loci. Antisense lncRNAs initiate inside or 3′ of a protein-coding gene, are transcribed in the opposite direction of proteincoding genes, and overlap at least one coding exon (THRIL, Fas-AS1, IL-1b–AS, TH2-LCR lncRNA). Intronic lncRNAs initiate inside of an intron of a protein-coding gene in either direction and terminate without overlapping exons (NRON). Divergent lncRNAs initiate in a divergent fashion from the promoter of a protein-coding gene; the precise distance cutoff constituting bidirectionality is not defined but is generally within a few hundred base pairs (GATA3-AS1). Intergenic lncRNAs (also termed long intergenic noncoding RNAs or lincRNAs) are lncRNAs with separate transcriptional units from protein-coding genes (IFNG-AS1 (NeST, Tmevpg1), lincRNA-Cox2, Lethe, lnc-DC, Linc-Ccr2-5′AS, PACER, linc-MAF-4, lincRNA-p21 (adapted from reference Rinn and Chang (2012)).
Fig. 3
Fig. 3
Cartoon model of IFNG-AS1 regulation and function (human genome is shown). TH1 differentiation signals, e.g. Stat4, T-bet, etc., cooperatively activate genomic proximal and distal enhancers selective for either IFNG or IFNGAS1. T-bet and IFNG-AS1 (blue arrow) cooperate to stimulate TH1-dependent IFNG transcription; IFNG-AS1 RNA recruits H3K4 histone methyltransferases to IFNG locus helping to maintain locus in a transcriptionally favorable state. Presence of IFNG-AS1 RNA is essential for robust expression of IFNG and resistance to Salmonella infection, in vivo, in mice.
Fig. 4
Fig. 4
Cartoon model of the TH2-LCR lncRNA. TH2 differentiation signals induce expression of TH2-LCR lncRNA isoforms. TH2-LCR lncRNA associates with the H3K4 methyltransferase enzyme complex and facilitates recruitment to IL4, IL13, and IL5 (perhaps) gene loci to establish H3K4 trimethylation marks at the promoters and distal enhancers of these genes creating a stimulatory transcriptional environment. The TH2-LCR lncRNA is required for expression of TH2 cytokines, IL-4, IL 13, and IL-5.
Fig. 5
Fig. 5
Example pipeline for identification and characterization of annotated and novel lncRNAs using whole genome sequencing.
See this image and copyright information in PMC

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