Long noncoding RNAs in innate immunity

Cellular & Molecular Immunology (2016) 13, 138–147 ß 2016 CSI and USTC. All rights reserved 1672-7681/16 $32.00 www.nature.com/cmi REVIEW Long noncoding RNAs in innate immunity Yuan Zhang and Xuetao Cao Long noncoding RNAs (lncRNAs) have been shown to play important roles in immune cell development and immune responses through different mechanisms, such as dosage compensation, imprinting, enhancer function, and transcriptional regulation. Although the functions of most lncRNAs are unclear, some lncRNAs have been found to control transcriptional or post-transcriptional regulation of the innate and adaptive immune responses via new methods of protein–protein interactions or pairing with DNA and RNA. Interestingly, increasing evidence has elucidated the importance of lncRNAs in the interaction between hosts and pathogens. In this review, an overview of the lncRNAs modes of action, as well as the important and diversified roles of lncRNAs in immunity, are provided, and an emerging paradigm of lncRNAs in regulating innate immune responses is highlighted. Cellular & Molecular Immunology (2016) 13, 138-147; doi:10.1038/cmi.2015.68; published online 17 August 2015 Keywords: host–pathogen interaction; innate immunity; long noncoding RNA ( INTRODUCTION Advances in high-throughput deep sequencing of the transcriptome and the ENCODE project1,2 have led to the discovery of numerous new noncoding RNAs (ncRNAs), including snRNAs (small nuclear RNAs), miRNAs (microRNAs), and lncRNAs (long noncoding RNA), which opened the ‘‘dark energy’’ of DNA.3,4 The ENCODE project explores all functional elements in human DNA and estimates that 80% of DNA is functional, while 62% is transcribed into ncRNA. lncRNA is defined based on its size (more than 200 nucleotides) and non-protein-coding capability.5 With the discovery of RNA interference, ncRNAs first came to prominence in the 1990s and studies have since revealed their roles in gene silencing and biological functions. With the progress of new technologies, such as microarrays and high-throughput sequencing, the Human Genome Project and the ENCODE project opened a new era of genetics at an unprecedented rate. Earlier evolutionary studies concluded that ncRNAs bear no evidence of function, as a result of poorly conserved sequences, which are conventionally subject to the product of transcriptional noise. However, ncRNAs have been demonstrated to be the ‘‘dark energy’’ of DNA.3,4 The evolution of ncRNAs is different from protein-coding genes, which conclude various scenarios for the origins of functional ncRNAs. Several classifications6 can be defined, including (i) gene frame disruptions and transformation into a functional ncRNA (such as the Xist7 lncRNA), (ii) untranscribed and separated sequence regions that juxtapose following the chromosome’s rearrangement, (iii) retrotransposition to generate either retrogenes or retropseudogenes, (iv) tandem duplication in neighboring gene repeats, and (v) insertion of a transposable elements. However, numerous lncRNAs are unknown, and the classifications of lncRNAs are based on their location and proximity to protein-coding genes. lncRNAs are defined as ncRNAs that are transcribed by RNA polymerase II, are at least 200 nucleotides in length, and do not have the ability to code proteins. Empirically, lncRNAs are classified according to their position relative to protein-coding genes, which are operationally divided into five classes:8,9 (i) intronic lncRANs are located within an intron of a proteincoding gene in either direction and terminate without overlapping exons; (ii) long intergenic ncRNAs (lincRNA) are separated by transcriptional units from protein-coding genes; (iii) bidirectional lncRNAs are transcribed in opposite directions in relation to the promoter of a protein-coding gene; (iv) antisense lncRNAs are transcribed across the exons of proteincoding genes from the opposite direction; and (v) transcribed pseudogene lncRNAs are transcribed from a gene without the ability to produce a protein. Although many lncRNAs are perceived to lack coding potential, it was unexpected that some of National Key Laboratory of Medical Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China Correspondence: Dr. X Cao, National Key Laboratory of Medical Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China. E-mail: Received: 12 June 2015; Accepted: 13 June 2015 Long noncoding RNAs in innate immunity Y Zhang and X Cao 139 them could encode small peptides in different tissues and species. Lauressergues et al.10 showed that pri-miR171b and primiR165a can produce peptides that trigger the accumulation of miR171b and miR165a. The molecular functions and mechanisms of lncRNAs have been described in several comprehensive reviews.11,12 The precise sequence and natural structure of lncRNAs mostly determine what that they interact with. Through employing RNA–RNA, RNA–DNA, or RNA–protein interactions, lncRNAs produce various processes to regulate transcription, splicing, nucleic acid degradation, decoy, and translation. lncRNAs are expressed in specific cell types and different cellular locations (nuclear or cytosolic), which determine their molecular function mechanisms. Additionally, their expression is under considerable transcriptional control. In the cytosol, lncRNAs not only interact directly with target RNAs to control their expression and mRNA translation but also interact with specific signaling proteins to regulate their pathway-specific gene expression programs. By contrast, nucleic lncRNAs play important roles in modulating epigenetic13,14 and transcriptional processes15 to regulate gene expression by acting as signal, guide, decoy, or scaffold. As molecular signals, lncRNAs can faithfully mark the time, space, developmental stage, and expression of gene regulation, which combine the actions of transcription factors and signaling pathways to regulate gene expression and subsequent biological events. As decoys, lncRNAs are transcribed and then titrate proteins, transcription factors, regulatory factors, or epigenetic modifiers (such as Gas516 and Lethe17). They can also decoy miRNAs and splicing factors that function as molecular sponges. As guides, lncRNAs can recruit chromatin modifiers in cis (co-transcription or as complementary regulatory RNAs) or trans conformations by binding to target DNA (heteroduplex, RNA:DNA or triplex, RNA:DNA:DNA, or specific recognition of chromatin). As scaffolds, lncRNAs can act as central platforms that bring and bind to multiple proteins or nucleotides, which function on chromatin by altering histone modifications and stabilize nuclear structures or signaling complexes. The mechanisms of gene regulation by lncRNAs are intricate and complicated, and lncRNAs themselves possess different sequences, do (...truncated)