Long non-coding RNAs and control of gene expression in the immune system

Abstract

All cells of the immune system rely on a highly integrated and dynamic gene expression program that is controlled by both transcriptional and post-transcriptional mechanisms. Recently, non-coding RNAs, including long non-coding RNAs (lncRNAs), have emerged as important regulators of gene expression in diverse biological contexts. lncRNAs control gene expression in the nucleus by modulating transcription or via post-transcriptional mechanisms targeting the splicing, stability, or translation of mRNAs. Our knowledge of lncRNA biogenesis, their cell type-specific expression, and their versatile molecular functions is rapidly progressing in all areas of biology. We discuss here these exciting new regulators and highlight an emerging paradigm of lncRNA-mediated control of gene expression in the immune system.

Keywords: epigenetics; gene expression; innate immunity; lincRNA; lncRNA; long non-coding RNA.

Figure 1

Long non-coding RNAs (lncRNAs) are the most abundant ncRNA species in the mammalian genome. (A) Pie charts showing the genome-wide distribution of protein- and non-coding genes in the human and mice genomes. Numbers shown are calculated from the GENCODE version 19 (July 2013 update; http://www.gencodegenes.org). (B) Classification of lncRNAs based on their genomic localization with respect to the neighboring protein-coding gene. LncRNAs in general are classified as non-overlapping (or the intergenic lncRNA; lincRNAs), or the overlapping lncRNAs, which include intronic and antisense (AS) lncRNAs. Intronic lncRNAs are transcribed within the intron of a protein-coding gene, and therefore do not contain sequences complementary to the mature, spliced mRNA of the protein-coding gene. Antisense lncRNA, however, contains region(s) of complementary sequences with the mature, spliced mRNA of the overlapping protein-coding gene. Examples of immune-related lncRNAs from the different lncRNA sub-classes are provided. Abbreviations: miRNA, micro-RNA; ncRNA, non-coding RNA; snRNA, small nuclear RNA; snoRNA, small nucleolar RNA.

Figure 2

Long non-coding RNAs (lncRNAs) are versatile regulators of gene expression. lncRNAs employ three basic modules, RNA–RNA, RNA–protein and RNA–DNA interactions, to exert their functions either in the cytosol (A,B) or the nucleus (C–E). (A) In the cytosol lncRNAs interact with target mRNAs through base-pairing to either enhance translation (e.g., Uchl1 AS), or repress translation (e.g., lincRNA-p21). In addition, cytosolic lncRNAs are also known to regulate mRNA stability. For example, the lncRNA termed ½-Staufen binding site (sbs) RNA forms an RNA duplex with mRNAs containing partial complementarity in the 3′-untranslated region (UTR) to promote Staufen 1 binding, which drives Staufen-mediated mRNA degradation. (B) Cytosolic lncRNAs are also known to regulate immune signaling pathways through RNA–protein interactions. NRON and lnc-DC act as a scaffold for the transcription factors NFAT and Stat3, respectively, regulating phosphorylation status and thereby the expression of target genes in immune cells. (C–E) In the nucleus, lncRNAs function by acting as a guide (C, NeST; THRIL), decoy (D, Lethe), or scaffold (E, lincRNA-Cox2) to interact with specific protein(s) to silence gene expression. Abbreviations: hnRNP, heterogeneous ribonucleoprotein; IQGAP, IQ motif-containing GTPase activating protein; MD1, muscle differentiation 1; NFAT, nuclear factor of activated T cells; NRON, non-coding repressor of NFAT; THRIL, TNFα and hnRNPL related immunoregulatory lincRNA; Uchl1, ubiquitin carboxy-terminal hydrolase L1; WDR5, WD repeat-containing protein 5.