Immunobiology of Long Noncoding RNAs

Abstract

The discovery of long noncoding RNAs (lncRNA) has provided a new perspective on gene regulation in diverse biological contexts. lncRNAs are remarkably versatile molecules that interact with RNA, DNA, or proteins to promote or restrain the expression of protein-coding genes. Activation of immune cells is associated with dynamic changes in expression of genes, the products of which combat infectious microorganisms, initiate repair, and resolve inflammatory responses in cells and tissues. Recent evidence indicates that lncRNAs play important roles in directing the development of diverse immune cells and controlling the dynamic transcriptional programs that are a hallmark of immune cell activation. The importance of these molecules is underscored by their newly recognized roles in inflammatory diseases. In this review, we discuss the contribution of lncRNAs in the development and activation of immune cells and their roles in immune-related diseases. We also discuss challenges faced in identifying biological functions for this large and complex class of genes.

Keywords: gene regulation; immunity; lincRNA; lncRNA; noncoding RNA.

Figure 1.. Classification and abundance of lncRNA genes.

(A) The classification of lncRNAs based on their genomic location with respect to nearby protein-coding genes. An intergenic lncRNA (lincRNA) is located between two protein-coding genes. All other sub-types of lncRNAs exhibit some degree of overlap with another gene located either on the same or opposite strand. Such lncRNAs may contains region(s) of complementary sequences with the mature, spliced mRNA of the overlapping protein-coding gene (antisense lncRNA), or 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. (B) The abundance of protein- and noncoding genes in the human genome. The data represents the latest GENCODE estimates (version 21) (http://www.gencodegenes.org). miRNA: micro-RNA; snRNA: small nuclear RNA; snoRNA: small nucleolar RNA.

Figure 1.. Classification and abundance of lncRNA genes.

(A) The classification of lncRNAs based on their genomic location with respect to nearby protein-coding genes. An intergenic lncRNA (lincRNA) is located between two protein-coding genes. All other sub-types of lncRNAs exhibit some degree of overlap with another gene located either on the same or opposite strand. Such lncRNAs may contains region(s) of complementary sequences with the mature, spliced mRNA of the overlapping protein-coding gene (antisense lncRNA), or 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. (B) The abundance of protein- and noncoding genes in the human genome. The data represents the latest GENCODE estimates (version 21) (http://www.gencodegenes.org). miRNA: micro-RNA; snRNA: small nuclear RNA; snoRNA: small nucleolar RNA.

Figure 2.. lncRNAs in the development and functions of myeloid cells.

(A) lncRNAs (e.g. H19, Xist, and lnc-HSC1 and lnc-HSC2) regulate the quiescence and the self-renewal of hematopoietic stem cells (HSC), and their differentiation into specific myeloid cell lineages, including DCs (lnc-DC), short-lived myeloid cells such as neutrophils, eosinophils and monocytes (Morrbid), and erythrocytes (lincRNA-EPS and alncRNA-EC7). Examples of lncRNAs that regulate the functions of specific myeloid cell lineages such as macrophages (e.g. lincRNA-Cox2, PACER, THRIL and lincRNA-EPS) are also illustrated. (B) lncRNAs represent a novel layer of the regulatory circuit that controls the inflammatory response of innate immune cells. The activation of intracellular signaling pathways (e.g. NF-κB) upon TLR or cytokine receptor engagement in innate immune cells (e.g. macrophage, DCs or epithelial cells) elaborates immune responses through a highly coordinated program of gene expression. These pathways can also induce the expression of lncRNAs in specific cell-type(s) to turn on a lncRNA-directed regulatory circuit, which acts in a “feed-forward” (e.g. PACER, THRIL and AS-IL1α), “negative feedback” (e.g. Lethe and NKILA), or “release of suppression” (e.g. lincRNA-EPS and lnc-13) manner. HSC, hematopoietic stem cell; CMP, common myeloid progenitor; GMP, granulocyte-monocyte progenitor; MEP, megakaryocyte-erythrocyte progenitor.

Figure 3.. lncRNAs in the development and functions of lymphoid cells.

(A) lncRNAs regulate the development of specific lymphoid cells (e.g. lincRNA-MAF-4 in CD4+ T_H1 cells) as well their effector functions. Examples of functional lncRNAs in B cells and T cells are shown. (B-D) The mechanism of actions of lncRNAs in CD4+ T helper cells. NeST interacts with the histone methyltransferase WDR5 to regulate the transcription of the neighboring IFN-γ gene in T_H1 cells (B). lincRNA-MAF-4 silences the expression of the transcription factor c-MAF (associated with T_H2 polarization) by promoting chromatin-looping between the genomic loci containing lincRNA-MAF-4 and MAF genes spaced ~140 kb apart to recruiting the PRC2 (polycomb repressive complex 2) component EZH2, and the histone demethylase LSD1 at the MAF gene locus (B). The lincRNA-MAF-4:EZH2:LSD1 complex leads to the epigenetic silencing of MAF4 expression in cis to direct the differentiation of naïve CD4+ T cells into T_H1 cells. The lncRNA, RMRP, acts as a molecular scaffold to recruit DDX5 and RORγt to genes associated with the effector functions of T_H17 cells (C). The RMRP:DDX5:RORγt axis regulates the transcriptional induction of a subset (e.g. IL17A and IL17F) of T_H17 genes. CLP, common lymphoid progenitors; TFs, transcription factors.

Figure 4.. Mechanism of action for lncRNAs.

lncRNAs mediate their molecular functions through a multitude of mechanisms in cytoplasm (A) or the nucleus (B). In the cytoplasm, lncRNAs act through RNA-protein (e.g. NRON and lnc-DC) or RNA-RNA (e.g. Uchl1 AS and linc-MD1) interactions. NRON and lnc-DC act as molecular scaffolds for the transcription factors, NFAT and STAT3. Uchl1 AS interacts with target mRNAs through base-paring to enhance their translation. In the nucleus, lncRNAs can act in cis or trans (B). Morrbid interacts with PRC2 to repress the transcription of the neighboring gene, Bim (Bcl2l11), in cis in short-lived myeloid cells such as neutrophils and monocytes. lncRNAs can interact with their protein partners as guide (e.g. lincRNA-EPS: hnRNPL), scaffold (e.g. RMRP interaction with DDX5 and RORγt) or a decoy molecule (e.g. Lethe: NF-κB p65) to mediate their molecular functions. Uchl1, ubiquitin carboxy-terminal hydrolase L1; lMD1: muscle differentiation 1.