Search Results for: incrna

Tissue-Specific RNA-Seq in Human Evoked Inflammation Identifies Blood and Adipose LincRNA Signatures

Inappropriate transcriptional activation of innate immunity is a pathological feature of several cardiometabolic disorders, but little is known about inflammatory modulation of long intergenic noncoding RNAs (lincRNAs) in disease-relevant human tissues.

Researchers at the University of Pennsylvania applied deep RNA sequencing (>500 million filtered reads per sample) to blood and adipose during low-dose experimental endotoxemia (lipopolysaccharide) in a healthy human, with targeted replication in separate individuals undergoing endotoxemia (n=6), to identify inflammatory lincRNAs. A subset of these lincRNAs was examined for expression in adipocytes and monocytes, modulation in adipose of obese humans, and overlap with genome-wide association study signals for inflammatory and cardiometabolic traits. Of a stringent set of 4284 lincRNAs, ≈11% to 22% were expressed with 201 and 56 lincRNAs modulated by lipopolysaccharide in blood or adipose, respectively. Tissue-specific expression of a subset of 6 lipopolysaccharide-lincRNAs was replicated with lipopolysaccharide modulation confirmed for all 3 expressed in blood and 2 of 4 expressed in adipose. The broader generalizability of findings in blood of subject A was confirmed by RNA sequencing in 7 additional subjects. The researchers confirmed adipocytes and monocytes as potential cell-sources of selective lipopolysaccharide-regulated lincRNAs, and 2 of these, linc-DMRT2 (P=0.002) and linc-TP53I13 (P=0.01), were suppressed in adipose of obese humans. Finally, they provide examples of lipopolysaccharide-modulated lincRNAs that overlap single nucleotide polymorphisms that are associated with cardiometabolic traits.

lncRNA

These findings provide novel insights into tissue-level, inflammatory transcriptome regulation in cardiometabolic diseases. These are complementary to more usual approaches limited to interrogation of DNA variations.

  • Liu Y1, Ferguson JF, Xue C, Ballantyne RL, Silverman IM, Gosai SJ, Serfecz J, Morley MP, Gregory BD, Li M, Reilly MP. (2014) Tissue-Specific RNA-Seq in Human Evoked Inflammation Identifies Blood and Adipose LincRNA Signatures of Cardiometabolic Diseases. Arterioscler Thromb Vasc Biol 34(4), 902-12. [abstract]

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lincRNAs are required for life

lncRNA

Many studies are uncovering functional roles for long noncoding RNAs (lncRNAs), yet few have been tested for in vivo relevance through genetic ablation in animal models. To investigate the functional relevance of lncRNAs in various physiological conditions, a team led by researchers at Harvard University have developed a collection of 18 lncRNA knockout strains in which the locus is maintained transcriptionally active. Initial characterization revealed peri- and postnatal lethal phenotypes in three mutant strains (Fendrr, Peril, and Mdgt), the latter two exhibiting incomplete penetrance and growth defects in survivors. The team also report growth defects for two additional mutant strains (linc-Brn1b and linc-Pint). Further analysis revealed defects in lung, gastrointestinal tract, and heart in Fendrr(-/-) neonates, whereas linc-Brn1b(-/-) mutants displayed distinct abnormalities in the generation of upper layer II-IV neurons in the neocortex. This study demonstrates that lncRNAs play critical roles in vivo and provides a framework and impetus for future larger-scale functional investigation into the roles of lncRNA molecules.

  • Sauvageau M et al. (2013) Multiple knockout mouse models reveal lincRNAs are required for life and brain development. Elife 2(0), e01749. [article]

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Genome-wide survey by ChIP-seq reveals YY1 regulation of lincRNAs in skeletal myogenesis

lncRNA

Skeletal muscle differentiation is orchestrated by a network of transcription factors, epigenetic regulators, and non-coding RNAs. The transcription factor Yin Yang 1 (YY1) silences multiple target genes in myoblasts (MBs) by recruiting Ezh2 (Enhancer of Zeste Homologue2). To elucidate genome-wide YY1 binding in MBs, we performed chromatin immunoprecipitation (ChIP)-seq and found 1820 specific binding sites in MBs with a large portion residing in intergenic regions. Detailed analysis demonstrated that YY1 acts as an activator for many loci in addition to its known repressor function. No significant co-occupancy was found between YY1 and Ezh2, suggesting an additional Ezh2-independent function for YY1 in MBs. Further analysis of intergenic binding sites showed that YY1 potentially regulates dozens of large intergenic non-coding RNAs (lincRNAs), whose function in myogenesis is underexplored.

Researchers from The Chinese University of Hong Kong characterized a novel muscle-associated lincRNA (Yam-1) that is positively regulated by YY1. Yam-1 is downregulated upon differentiation and acts as an inhibitor of myogenesis. They demonstrate that Yam-1 functions through in cis regulation of miR-715, which in turn targets Wnt7b. These findings not only provide the first genome-wide picture of YY1 association in muscle cells, but also uncover the functional role of lincRNA Yam-1.

  • Lu L, Sun K, Chen X, Zhao Y, Wang L, Zhou L, Sun H, Wang H. (2013) Genome-wide survey by ChIP-seq reveals YY1 regulation of lincRNAs in skeletal myogenesis. EMBO J [Epub ahead of print]. [abstract]

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Featured Long Non-coding RNA – lincRNA-Cox2

lincRNA

An inducible program of inflammatory gene expression is central to antimicrobial defenses. Signal-dependent activation of transcription factors, transcriptional co-regulators, and chromatin modifying factors collaborate to control this response. Here, researchers from University of Massachusetts Medical School identify a long noncoding RNA that acts as a key regulator of this inflammatory response. Pattern recognition receptors such as the Toll-like receptors induce the expression of numerous lncRNAs. One of these, lincRNA-Cox2 mediates both the activation and repression of distinct classes of immune genes. Transcriptional repression of target genes is dependent on interactions of lincRNA-Cox2 with heterogeneous nuclear ribonucleoprotein A/B and A2/B1. Collectively, these studies unveil a central role of lincRNA-Cox2 as a broad acting regulatory component of the circuit that controls the inflammatory response.

  • Carpenter S, Atianand M, Aiello D, Ricci EP, Gandhi P, Hall LL, Byron M, Monks B, Henry-Bezy M, Lawrence JB, O’Neill LA, Moore MJ, Caffrey DR, Fitzgerald KA. (2013) A Long Noncoding RNA Mediates Both Activation and Repression of Immune Response Genes. Science [Epub ahead of print]. [abstract]

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vlincRNAs: very long intergenic non-coding RNAs

lncRNAs

The function of the non-coding portion of the human genome remains one of the most important questions of our time. Its vast complexity is exemplified by the recent identification of an unusual and notable component of the transcriptome – very long intergenic non-coding RNAs, termed vlincRNAs.

Here a team led by researchers from the St. Laurent Institute identify 2,147 vlincRNAs covering 10 percent of our genome. They show they are present not only in cancerous cells, but also in primary cells and normal human tissues, and are controlled by canonical promoters. Furthermore, vlincRNA promoters frequently originate from within endogenous retroviral sequences. Strikingly, the number of vlincRNAs expressed from endogenous retroviral promoters strongly correlates with pluripotency or the degree of malignant transformation. These results suggest a previously unknown connection between the pluripotent state and cancer via retroviral repeat-driven expression of vlincRNAs. Finally, they show that vlincRNAs can be syntenically conserved in humans and mouse and their depletion using RNAi can cause apoptosis in cancerous cells.

  • St Laurent G 3rd, Shtokalo D, Dong B, Tackett MR, Fan X, Lazorthes S, Nicolas E, Sang N, Triche TJ, McCaffrey TA, Xiao W, Kapranov P. (2013) VlincRNAs controlled by retroviral elements are a hallmark of pluripotency and cancer. Genome Biol 14(7), R73. [abstract]

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