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Key Points Although long non-coding RNAs (lncRNAs) and mRNAs share many common features, several types of lncRNAs are distinguished from mRNAs by unique features of biogenesis, form and function. lncRNAs exhibit more highly specific expression patterns than mRNAs. Many lncRNAs undergo special processing events, such as backspliced circularization, 5′- and 3′-bookending by processed small nucleolar RNAs (snoRNAs), and cleavage by RNase P. lncRNAs are more enriched in the nucleus than the cytoplasm relative to mRNAs, and although cytoplasmic lncRNAs associate with the ribosome, few are productively translated. Certain classes of lncRNAs are preferentially subject to degradation by nonsense-mediated decay and the nuclear exosome, and the elongation of divergent ncRNA transcripts is co-transcriptionally terminated by premature polyadenylation. lncRNAs are uniquely capable of cis action on the genome and chromatin. This feature of lncRNAs enables such biological phenomena as gene imprinting, dosage compensation of sex chromosomes, transcriptional enhancement, chromosome looping and antisense regulation. Long non-coding RNAs (lncRNAs) are a class of RNAs with great molecular and regulatory diversity. This Review discusses how, beyond their lack of protein-coding potential, some types of lncRNAs are known to exhibit features that are distinct from mRNAs, including their transcriptional regulation, localization, processing, biological capabilities and degradation. Such properties underlie many of the key cellular functions of lncRNAs. Long non-coding RNAs (lncRNAs) are a diverse class of RNAs that engage in numerous biological processes across every branch of life. Although initially discovered as mRNA-like transcripts that do not encode proteins, recent studies have revealed features of lncRNAs that further distinguish them from mRNAs. In this Review, we describe special events in the lifetimes of lncRNAs — before, during and after transcription — and discuss how these events ultimately shape the unique characteristics and functional roles of lncRNAs.

Cancers arise through the accumulation of genetic and epigenetic alterations that enable cells to evade telomere-based proliferative barriers and achieve immortality. One such barrier is replicative crisis—an autophagy-dependent program that eliminates checkpoint-deficient cells with unstable telomeres and other cancer-relevant chromosomal aberrations 1 , 2 . However, little is known about the molecular events that regulate the onset of this important tumour-suppressive barrier. Here we identified the innate immune sensor Z-DNA binding protein 1 (ZBP1) as a regulator of the crisis program. A crisis-associated isoform of ZBP1 is induced by the cGAS–STING DNA-sensing pathway, but reaches full activation only when associated with telomeric-repeat-containing RNA (TERRA) transcripts that are synthesized from dysfunctional telomeres. TERRA-bound ZBP1 oligomerizes into filaments on the outer mitochondrial membrane of a subset of mitochondria, where it activates the innate immune adapter protein mitochondrial antiviral-signalling protein (MAVS). We propose that these oligomerization properties of ZBP1 serve as a signal amplification mechanism, where few TERRA–ZBP1 interactions are sufficient to launch a detrimental MAVS-dependent interferon response. Our study reveals a mechanism for telomere-mediated tumour suppression, whereby dysfunctional telomeres activate innate immune responses through mitochondrial TERRA–ZBP1 complexes to eliminate cells destined for neoplastic transformation. Dysfunctional telomeres activate innate immune responses through mitochondrial TERRA–ZBP1 complexes to eliminate cells that are destined for neoplastic transformation.

Gene maps, or annotations, enable us to navigate the functional landscape of our genome. They are a resource upon which virtually all studies depend, from single-gene to genome-wide scales and from basic molecular biology to medical genetics. Yet present-day annotations suffer from trade-offs between quality and size, with serious but often unappreciated consequences for downstream studies. This is particularly true for long non-coding RNAs (lncRNAs), which are poorly characterized compared to protein-coding genes. Long-read sequencing technologies promise to improve current annotations, paving the way towards a complete annotation of lncRNAs expressed throughout a human lifetime.

The exciting world of research with RNAs has to its credit some breakthrough findings that led to newer insights on multiple problems including that of human diseases. After the advent of siRNA, microRNA, and lncRNA, exciting novel molecules called circular RNAs (circRNAs) have been recently described. circRNAs are a class of non-coding RNAs, which are produced by scrambling of exons at the time of splicing. They are primarily produced in the brain region and are naturally present inside the cell. The best known ones so far include a particular type of circRNA namely “circular RNA sponge for miR-7” (ciRS-7 and CDR1as) which is the inhibitor of miR-7 microRNA—known to regulate various diseases like, cancer, neurodegenerative diseases, diabetes, and atherosclerosis. Similarly, another circRNA molecule called circmbl modulates the ratio of linear mRNA by competing with linear muscleblind gene through which it is synthesized. Considering the complex association of these molecules with critical microRNAs and gene families, circRNAs might have important roles in the cause and progression of human diseases. In particular, the multi-factorial nature of neurodegenerative diseases does warrant studies employing novel approaches towards identifying underlying root causes of these ailments. The non-coding RNAs, like circRNAs and microRNAs, could well present a common genetic trigger to multiple factors associated with neurodegenerative diseases. A specific fingerprint of a combination of various marker circRNAs could be explored for early diagnostic purpose as well. Herein, we review the possibility of exploring the role of circRNAs in the context of the central nervous system (CNS) and age-associated neurodegenerative diseases.

Zhao and colleagues find that neuropathic pain is accompanied by an increase in the expression of an antisense long noncoding RNA (lncRNA) that downregulates Kcna2 currents and increases excitability in rat dorsal root ganglion neurons. Preventing the expression of the so-called Kcna2 antisense RNA mitigates neuropathic pain symptoms. Neuropathic pain is a refractory disease characterized by maladaptive changes in gene transcription and translation in the sensory pathway. Long noncoding RNAs (lncRNAs) are emerging as new players in gene regulation, but how lncRNAs operate in the development of neuropathic pain is unclear. Here we identify a conserved lncRNA, named Kcna2 antisense RNA, for a voltage-dependent potassium channel mRNA, Kcna2 , in first-order sensory neurons of rat dorsal root ganglion (DRG). Peripheral nerve injury increased Kcna2 antisense RNA expression in injured DRG through activation of myeloid zinc finger protein 1, a transcription factor that binds to the Kcna2 antisense RNA gene promoter. Mimicking this increase downregulated Kcna2, reduced total voltage-gated potassium current, increased excitability in DRG neurons and produced neuropathic pain symptoms. Blocking this increase reversed nerve injury–induced downregulation of DRG Kcna2 and attenuated development and maintenance of neuropathic pain. These findings suggest endogenous Kcna2 antisense RNA as a therapeutic target for the treatment of neuropathic pain.

Significance We provide a comprehensive catalog of novel genetic variants influencing gene expression and metabolic phenotypes in human pancreatic islets. The data also show that the path from genetic variation (SNP) to gene expression is more complex than hitherto often assumed, and that we need to consider that genetic variation can also influence function of a gene by influencing exon usage or splice isoforms (sQTL), allelic imbalance, RNA editing, and expression of noncoding RNAs, which in turn can influence expression of target genes. Genetic variation can modulate gene expression, and thereby phenotypic variation and susceptibility to complex diseases such as type 2 diabetes (T2D). Here we harnessed the potential of DNA and RNA sequencing in human pancreatic islets from 89 deceased donors to identify genes of potential importance in the pathogenesis of T2D. We present a catalog of genetic variants regulating gene expression (eQTL) and exon use (sQTL), including many long noncoding RNAs, which are enriched in known T2D-associated loci. Of 35 eQTL genes, whose expression differed between normoglycemic and hyperglycemic individuals, siRNA of tetraspanin 33 (TSPAN33), 5′-nucleotidase, ecto (NT5E), transmembrane emp24 protein transport domain containing 6 (TMED6), and p21 protein activated kinase 7 (PAK7) in INS1 cells resulted in reduced glucose-stimulated insulin secretion. In addition, we provide a genome-wide catalog of allelic expression imbalance, which is also enriched in known T2D-associated loci. Notably, allelic imbalance in paternally expressed gene 3 (PEG3) was associated with its promoter methylation and T2D status. Finally, RNA editing events were less common in islets than previously suggested in other tissues. Taken together, this study provides new insights into the complexity of gene regulation in human pancreatic islets and better understanding of how genetic variation can influence glucose metabolism.

This study demonstrates a role for the Integrator complex in the stimulus-dependent induction of eRNAs and their 3′ processing; together with previously known roles of Integrator in transcription elongation and RNA processing, these results indicate that Integrator has broad functions in the regulation of eukaryotic gene expression. Inducing enhancer RNAs Enhancer RNAs (eRNAs) are non-coding RNAs transcribed from active enhancers that seem to have a role in transcriptional induction of enhancer target genes. Here, Ramin Shiekhattar and colleagues demonstrate a role for the RNA polymerase II (RNAPII)-associated complex Integrator in the stimulus-dependent induction of eRNAs and their 3′ processing. Together with previously known roles of Integrator in transcription initiation and RNA processing, these results indicate that Integrator has broad functions in the regulation of eukaryotic gene expression. Integrator is a multi-subunit complex stably associated with the carboxy-terminal domain (CTD) of RNA polymerase II (RNAPII) 1 . Integrator is endowed with a core catalytic RNA endonuclease activity, which is required for the 3′-end processing of non-polyadenylated, RNAPII-dependent, uridylate-rich, small nuclear RNA genes 1 . Here we examine the requirement of Integrator in the biogenesis of transcripts derived from distal regulatory elements (enhancers) involved in tissue- and temporal-specific regulation of gene expression in metazoans 2 , 3 , 4 , 5 . Integrator is recruited to enhancers and super-enhancers in a stimulus-dependent manner. Functional depletion of Integrator subunits diminishes the signal-dependent induction of enhancer RNAs (eRNAs) and abrogates stimulus-induced enhancer–promoter chromatin looping. Global nuclear run-on and RNAPII profiling reveals a role for Integrator in 3′-end cleavage of eRNA primary transcripts leading to transcriptional termination. In the absence of Integrator, eRNAs remain bound to RNAPII and their primary transcripts accumulate. Notably, the induction of eRNAs and gene expression responsiveness requires the catalytic activity of Integrator complex. We propose a role for Integrator in biogenesis of eRNAs and enhancer function in metazoans.

Transcription of a long non-coding RNA, known as upperhand ( Uph ) located upstream of the HAND2 transcription factor is required to maintain transcription of the Hand2 gene by RNA polymerase, and blockade of Uph expression leads to heart defects and embryonic lethality in mice. upperhand regulates Hand2 expression in early cardiogenesis The expression of the transcription factor HAND2 is controlled by several upstream enhancer elements, confined in a region delimited by the presence of the chromatin mark H3K27Ac. Eric Olson and colleagues have found that the transcription of long non-coding RNA located upstream of HAND2 is required to maintained these chromatin marks and let the RNA polymerase transcribe the Hand2 gene. Preventing the expression of this long non-coding RNA with a termination cassette leads to defects in heart development in mice. HAND2 is an ancestral regulator of heart development and one of four transcription factors that control the reprogramming of fibroblasts into cardiomyocytes 1 , 2 , 3 , 4 . Deletion of Hand2 in mice results in right ventricle hypoplasia and embryonic lethality 1 , 5 . Hand2 expression is tightly regulated by upstream enhancers 6 , 7 that reside within a super-enhancer delineated by histone H3 acetyl Lys27 (H3K27ac) modifications 8 . Here we show that transcription of a Hand2- associated long non-coding RNA, which we named upperhand ( Uph ), is required to maintain the super-enhancer signature and elongation of RNA polymerase II through the Hand2 enhancer locus. Blockade of Uph transcription, but not knockdown of the mature transcript, abolished Hand2 expression, causing right ventricular hypoplasia and embryonic lethality in mice. Given the substantial number of uncharacterized promoter-associated long non-coding RNAs encoded by the mammalian genome 9 , the Uph – Hand2 regulatory partnership offers a mechanism by which divergent non-coding transcription can establish a permissive chromatin environment.

The adenomatous polyposis coli (APC) gene plays a pivotal role in the pathogenesis of colorectal carcinoma (CRC) but remains a challenge for drug development. Long noncoding RNAs (lncRNAs) are invaluable in identifying cancer pathologies and providing therapeutic options for patients with cancer. Here, we identified a lncRNA (lncRNA-APC1) activated by APC through lncRNA microarray screening and examined its expression in a large cohort of CRC tissues. A decrease in lncRNA-APC1 expression was positively associated with lymph node and/or distant metastasis, a more advanced clinical stage, as well as a poor prognosis for patients with CRC. Additionally, APC could enhance lncRNA-APC1 expression by suppressing the enrichment of PPARα on the lncRNA-APC1 promoter. Furthermore, enforced lncRNA-APC1 expression was sufficient to inhibit CRC cell growth, metastasis, and tumor angiogenesis by suppressing exosome production through the direct binding of Rab5b mRNA and a reduction of its stability. Importantly, exosomes derived from lncRNA-APC1-silenced CRC cells promoted angiogenesis by activating the MAPK pathway in endothelial cells, and, moreover, exosomal Wnt1 largely enhanced CRC cell proliferation and migration through noncanonicial Wnt signaling. Collectively, lncRNA-APC1 is a critical lncRNA regulated by APC in the pathogenesis of CRC. Our findings suggest that an APC-regulated lncRNA-APC1 program is an exploitable therapeutic approach for the treatment of patients with CRC.

Background Long non-coding RNAs (lncRNAs) have been associated with non-small cell lung cancer (NSCLC), but the underlying molecular mechanisms of their specific roles in mediating aerobic glycolysis have been poorly explored. Methods Next-generation RNA sequencing assay was performed to identify the differentially expressed RNAs between NSCLC tissues with high 18 F-fluorodeoxyglucose (FDG) uptake and their adjacent normal lung tissues. LINC01123 expression in NSCLC tissues was measured by real-time PCR and in situ hybridization (ISH) assay. The biological role of LINC01123 in cell growth and aerobic glycolysis capability was determined by performing functional experiments in vitro and in vivo. Further, the transcription of LINC01123 was explored by bioinformatics analysis, dual-luciferase reporter assay, and chromatin immunoprecipitation (ChIP) assay. RNA immunoprecipitation (RIP) and luciferase analyses were used to confirm the predicted competitive endogenous RNA (ceRNA) mechanisms between LINC01123 and c-Myc. Results Three hundred sixty-four differentially expressed genes were identified in RNA-seq assay, and LINC01123 was one of the most overexpressed lncRNAs. Further validation in expanded NSCLC cohorts confirmed that LINC01123 was upregulated in 92 paired NSCLC tissues and associated with poor survival. Functional assays showed that LINC01123 promoted NSCLC cell proliferation and aerobic glycolysis. Mechanistic investigations revealed that LINC01123 was a direct transcriptional target of c-Myc. Meanwhile, LINC01123 increased c-Myc mRNA expression by sponging miR-199a-5p. In addition, rescue experiments showed that LINC01123 functioned as an oncogene depending on miR-199a-5p and c-Myc. Conclusion Since LINC01123 is upregulated in NSCLC, correlates with prognosis, and controls proliferation and aerobic glycolysis by a positive feedback loop with c-Myc, it is expected to be a potential biomarker and therapeutic target for NSCLC.