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Review
. 2015 Feb;36(1):25-64.
doi: 10.1210/er.2014-1034. Epub 2014 Nov 26.

From discovery to function: the expanding roles of long noncoding RNAs in physiology and disease

Miao Sun  1 , W Lee Kraus
Affiliations
Review

From discovery to function: the expanding roles of long noncoding RNAs in physiology and disease

Miao Sun et al. Endocr Rev. 2015 Feb.

Abstract

Long noncoding RNAs (lncRNAs) are a relatively poorly understood class of RNAs with little or no coding capacity transcribed from a set of incompletely annotated genes. They have received considerable attention in the past few years and are emerging as potentially important players in biological regulation. Here we discuss the evolving understanding of this new class of molecular regulators that has emerged from ongoing research, which continues to expand our databases of annotated lncRNAs and provide new insights into their physical properties, molecular mechanisms of action, and biological functions. We outline the current strategies and approaches that have been employed to identify and characterize lncRNAs, which have been instrumental in revealing their multifaceted roles ranging from cis- to trans-regulation of gene expression and from epigenetic modulation in the nucleus to posttranscriptional control in the cytoplasm. In addition, we highlight the molecular and biological functions of some of the best characterized lncRNAs in physiology and disease, especially those relevant to endocrinology, reproduction, metabolism, immunology, neurobiology, muscle biology, and cancer. Finally, we discuss the tremendous diagnostic and therapeutic potential of lncRNAs in cancer and other diseases. VSports手机版.

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Figures

Figure 1.
Figure 1.
Molecular features of lncRNAs. LncRNAs are generally, but not exclusively, transcribed by RNA Pol II, spliced, 5′-capped (m7G), and 3′-polyadenylated (AAAAAA). By definition, they have a mature length of >200 nt, and low or no coding potential.
Figure 2.
Figure 2.
Biogenesis of lncRNAs. A, LncRNAs can be intergenic or genic (approximately one-third to one-half of lncRNAs overlap a protein-coding gene). Some intergenic lncRNAs are transcribed divergently to a protein-coding gene. Genic lncRNAs can be further divided into those that overlap a protein-coding gene in the sense vs antisense direction, and overlap exonic or intronic regions of a protein-coding gene. B, Many lncRNAs are transcribed and processed like mRNAs, whereas others originate from atypical processing of RNA transcripts. CircRNAs originate from back-spliced exons, whereas ciRNAs originate from lariat introns that escape from debranching. Sno-lncRNAs are processed on both ends by the snoRNA (sno) machinery, but retain the sequences between the snoRNAs, leading to the production of lncRNAs flanked by snoRNA sequences on either side, but lacking 5′-caps and 3′-polyadenosine tails.
Figure 3.
Figure 3.
Omics approaches for identifying and annotating lncRNAs. A, Primary lncRNA transcripts are produced from lncRNA genes and are further processed to mature lncRNA transcripts. B, A variety of omics approaches have been used to identify and annotate lncRNA genes and transcripts, including ChIP-seq for histone modifications (H3K4me3, which marks active promoters, and H3K36me3, which marks transcribed gene bodies), GRO-seq, RNA-seq, and others, as illustrated. Abbreviations: TTS, transcription termination site; CAGE, cap analysis of gene expression; RACE, rapid amplification of cDNA ends.
Figure 4.
Figure 4.
Guilt-by-association analyses link lncRNA expression patterns to gene ontologies and pathways through mRNA expression patterns. A, Overview of the guilt-by-association approach. B, The RNA correlation matrix links the expression of each lncRNA to the expression of all mRNAs (and their associated pathways and ontologies). C, The guilt-by-association matrix links pathways with each lncRNAs through gene set enrichment analyses. The assumption is lncRNAs that share expression patterns with mRNAs will also share pathways and ontologies. D, A heatmap provides a graphical representation of the results from the guilt-by-association matrix, showing significant positive and negative correlation between each lncRNA and each pathway. Hierarchical clustering groups lncRNAs that have similar expected functions. Abbreviations: pos., positive; neg., negative.
Figure 5.
Figure 5.
LncRNA-protein interactions drive molecular outcomes in gene regulation. Some lncRNAs function as molecular scaffolds that promote the assembly of complexes containing chromatin- and transcription-modulating factors. These interactions are driven by specific interactions between lncRNAs and proteins. The schematic diagram illustrates and generalizes specific lncRNA-protein interactions that have been observed in specific gene regulation contexts. From left to right: The lncRNA ecCEBPA interacts with the DNA methyltransferase DNMT1 to block DNA methylation and control gene expression outcomes (121). H19 binds to the methyl-CpG-binding protein MBD1 to control gene expression by recruiting a histone lysine methyltransferase (KMT) to add repressive histone marks to the differentially methylated regions of imprinted genes (122). Wrap53, a natural antisense transcript of TP53, interacts with the insulator protein and transcriptional regulator CTCF to control gene expression (123). CTCF also interacts with SRA and its associated DEAD-box RNA helicase p68 to form a complex with CTCF that is essential for insulator function (124). ncRNA-a lncRNAs interact with the Med12 subunit of the Mediator complex to promote gene looping and target gene activation (102). HOTAIR interacts with the histone methyltransferase Ezh2, a key component of the PRC2 complex, to mediate chromatin-dependent gene regulation (21, 107, 112). HOTAIR also interacts with Jarid2, a PRC2-associated factor, to promote the targeting of PRC2 to chromatin (116, 117). THRIL binds to hnRNPL, a component of hnRNP complexes, and the THRIL-hnRNPL complex regulates transcription by binding to target gene promoters (125).
Figure 6.
Figure 6.
Gene regulation by lncRNAs occurs through nuclear and cytoplasmic mechanisms that affect transcriptional, posttranscriptional, and translational events. LncRNAs mediate their functional roles by regulating gene expression at many different levels, through a variety of molecular mechanisms both in the nucleus and in the cytoplasm. The nuclear functions of lncRNAs include interactions with chromatin-modifying complexes to alter epigenetic modifications (A); interactions with transcription factors (TFs) (B), such as nuclear receptors (NRs), and additional transcriptional coregulators, to alter their gene regulatory activities; and actions as molecular decoys to titrate away and inhibit the activity of DNA-binding TFs (C). The cytoplasmic functions of lncRNAs include sponging of microRNAs to reduce microRNA targeting of mRNAs (D), as in the case of ceRNAs; interactions with STAU1 and regulation of STAU1-dependent mRNA stability (E); and interactions with the cytoplasmic RNA-binding protein Rck/p54 to inhibit translation (F).
Figure 7.
Figure 7.
Physiological and pathophysiological functions of lncRNAs. Recent studies have identified important roles for lncRNAs in the physiology and pathophysiology of the endocrine, reproductive, metabolic, immune, nervous, and cardiovascular systems in both females and males. Moreover, lncRNAs are emerging as key regulators of cell proliferation and cell death, which are often associated with cancer.
Figure 8.
Figure 8.
LncRNAs act as regulators, coregulators, and modulators of nuclear receptors. A number of lncRNAs have been implicated in the regulation of nuclear receptor (NR) functions, ultimately controlling receptor-mediated transcriptional programs. The regulation occurs through direct interactions with NR-associated coactivators and corepressors (as in the case of the lncRNAs SRA and CTBP1-as) (illustrations 1 and 2), direct interactions with NRs (as in the case of the lncRNAs GAS5, PRNCR1, and PCGEM1) (illustration 3), and additional transcriptional mechanisms acting either upstream or downstream of the NRs (eg, PR antisense transcripts, estrogen-regulated lncRNAs) (illustration 4).
Figure 9.
Figure 9.
A possible integrated lncRNA network controlling inflammatory responses. Schematic representation of known proinflammatory (A and C) and anti-inflammatory (B) gene regulatory responses. Although the specific interrelationships illustrated here are not specifically known, they are inferred from the literature. A, The lncRNA THRIL regulates the expression of TNFA, the gene encoding TNFα (125), a key proinflammatory cytokine. B, LincRNA-Cox2, one of the most highly upregulated lincRNAs in Tlr4-stimulated mouse dendritic cells bone marrow-derived macrophages (18), mediates both activation and repression of important inflammatory genes, such as those encoding cytokines and chemokines (253). This repression involves the formation of a lncRNA-protein complex containing lincRNA-Cox2 and hnRNP proteins (253). C, The expression of Lethe is regulated by the proinflammatory cytokine TNFα through the transcription factor NF-κB, a master regulator of inflammatory responses. Lethe acts as a negative regulator of NF-κB-dependent inflammatory signaling through physical interactions with the RelA subunit of NF-κB, forming a negative feedback loop to modulate inflammatory responses (254).
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