The subcellular localization of long noncoding RNAs (lncRNAs) holds valuable clues to their molecular function. However, measuring localization of newly discovered lncRNAs involves time-consuming and costly experimental methods. We have created "lncATLAS," a comprehensive resource of lncRNA localization in human cells based on RNA-sequencing data sets. Altogether, 6768 GENCODE-annotated lncRNAs are represented across various compartments of 15 cell lines. We introduce relative concentration index (RCI) as a useful measure of localization derived from ensemble RNA-seq measurements. LncATLAS is accessible through an intuitive and informative webserver, from which lncRNAs of interest are accessed using identifiers or names. Localization is presented across cell types and organelles, and may be compared to the distribution of all other genes. Publication-quality figures and raw data tables are automatically generated with each query, and the entire data set is also available to download. LncATLAS makes lncRNA subcellular localization data available to the widest possible number of researchers. It is available at lncatlas.crg.eu.
Recent footprinting studies have made the surprising observation that long noncoding RNAs (lncRNAs) physically interact with ribosomes. However, these findings remain controversial, and the overall proportion of cytoplasmic lncRNAs involved is unknown. Here we make a global, absolute estimate of the cytoplasmic and ribosome-associated population of stringently filtered lncRNAs in a human cell line using polysome profiling coupled to spike-in normalized microarray analysis. Fifty-four percent of expressed lncRNAs are detected in the cytoplasm. The majority of these (70%) have >50% of their cytoplasmic copies associated with polysomal fractions. These interactions are lost upon disruption of ribosomes by puromycin. Polysomal lncRNAs are distinguished by a number of 5 ′ mRNA-like features, including capping and 5 ′ UTR length. On the other hand, nonpolysomal "free cytoplasmic" lncRNAs have more conserved promoters and a wider range of expression across cell types. Exons of polysomal lncRNAs are depleted of endogenous retroviral insertions, suggesting a role for repetitive elements in lncRNA localization. Finally, we show that blocking of ribosomal elongation results in stabilization of many associated lncRNAs. Together these findings suggest that the ribosome is the default destination for the majority of cytoplasmic long noncoding RNAs and may play a role in their degradation.
The localization of long noncoding RNAs (lncRNAs) within the cell is the primary determinant of their molecular functions. LncRNAs are often thought of as chromatin-restricted regulators of gene transcription and chromatin structure. However, a rich population of cytoplasmic lncRNAs has come to light, with diverse roles including translational regulation, signaling, and respiration. RNA maps of increasing resolution and scope are revealing a subcellular world of highly specific localization patterns and hint at sequence-based address codes specifying lncRNA fates. We propose a new framework for analyzing sequencing-based data, which suggests that numbers of cytoplasmic lncRNA molecules rival those in the nucleus. New techniques promise to create high-resolution, transcriptome-wide maps associated with all organelles of the mammalian cell. Given its intimate link to molecular roles, subcellular localization provides a means of unlocking the mystery of lncRNA functions.
Long noncoding RNAs (lncRNAs) represent a vast unexplored genetic space that may hold missing drivers of tumourigenesis, but few such “driver lncRNAs” are known. Until now, they have been discovered through changes in expression, leading to problems in distinguishing between causative roles and passenger effects. We here present a different approach for driver lncRNA discovery using mutational patterns in tumour DNA. Our pipeline, ExInAtor, identifies genes with excess load of somatic single nucleotide variants (SNVs) across panels of tumour genomes. Heterogeneity in mutational signatures between cancer types and individuals is accounted for using a simple local trinucleotide background model, which yields high precision and low computational demands. We use ExInAtor to predict drivers from the GENCODE annotation across 1112 entire genomes from 23 cancer types. Using a stratified approach, we identify 15 high-confidence candidates: 9 novel and 6 known cancer-related genes, including MALAT1, NEAT1 and SAMMSON. Both known and novel driver lncRNAs are distinguished by elevated gene length, evolutionary conservation and expression. We have presented a first catalogue of mutated lncRNA genes driving cancer, which will grow and improve with the application of ExInAtor to future tumour genome projects.
Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder marked by relative resistance to steroids. Inflammation and apoptosis have been suggested to be important mechanisms for COPD. Interleukin (IL)-17 superfamily has been associated with chronic inflammation and diminished responses to steroids. It is reasonable to consider that IL-17 may play a role in the pathogenesis of COPD. In this study, we examined IL-17 expression in mice exposed to cigarette smoke (CS) and investigated the contribution of IL-17 to CS-induced inflammation and alveolar cell apoptosis in IL-17(-/-) mice. After exposing wild-type and IL-17(-/-) mice to mainstream CS for 4 wk, IL-17A, but not IL-17F, expression was increased in mice upon CS exposure. Neutrophil infiltration in the lungs of IL-17(-/-) mice was significantly decreased. In IL-17(-/-) mice, there is reduced expression of IL-6, macrophage inflammatory protein-2, and matrix metalloproteinase-12 compared with wild-type mice after CS exposure. The number of apoptotic type II alveolar cells was significantly increased in CS-exposed wild-type mice but not in IL-17(-/-) mice. The effect of IL-17A on type II alveolar cell apoptosis was confirmed in vitro through either addition of IL-17A or transient knockdown of IL-17A by small-interfering RNA transfection in type II alveolar cells. These findings suggest that IL-17A plays an important role in the inflammatory response to CS exposure through increased multiple inflammatory mediators. Moreover, IL-17 may also contribute to type II alveolar cell apoptosis. This study opens a new option in targeting IL-17A to modulate inflammatory response to CS and may be the bases for new therapy for COPD.
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Interest in the biological roles of long noncoding RNAs (lncRNAs) has resulted in growing numbers of studies that produce large sets of candidate genes, for example, differentially expressed between two conditions. For sets of protein-coding genes, ontology and pathway analyses are powerful tools for generating new insights from statistical enrichment of gene features. Here we present the LnCompare web server, an equivalent resource for studying the properties of lncRNA gene sets. The Gene Set Feature Comparison mode tests for enrichment amongst a panel of quantitative and categorical features, spanning gene structure, evolutionary conservation, expression, subcellular localization, repetitive sequences and disease association. Moreover, in Similar Gene Identification mode, users may identify other lncRNAs by similarity across a defined range of features. Comprehensive results may be downloaded in tabular and graphical formats, in addition to the entire feature resource. LnCompare will empower researchers to extract useful hypotheses and candidates from lncRNA gene sets.
The function of long noncoding RNAs (lncRNAs) depends on their location within the cell. While most studies to date have concentrated on their nuclear roles in transcriptional regulation, evidence is mounting that lncRNA also have cytoplasmic roles. Here we comprehensively map the cytoplasmic and ribosomal lncRNA population in a human cell. Three-quarters (74%) of lncRNAs are detected in the cytoplasm, the majority of which (62%) preferentially cofractionate with polyribosomes. Ribosomal lncRNA are highly expressed across tissues, under purifying evolutionary selection, and have cytoplasmic-to-nuclear ratios comparable to mRNAs and consistent across cell types. LncRNAs may be classified into three groups by their ribosomal interaction: non-ribosomal cytoplasmic lncRNAs, and those associated with either heavy or light polysomes. A number of mRNA-like features destin lncRNA for light polysomes, including capping and 5’UTR length, but not cryptic open reading frames or polyadenylation. Surprisingly, exonic retroviral sequences antagonise recruitment. In contrast, it appears that lncRNAs are recruited to heavy polysomes through basepairing to mRNAs. Finally, we show that the translation machinery actively degrades lncRNA. We propose that light polysomal lncRNAs are translationally engaged, while heavy polysomal lncRNAs are recruited indirectly. These findings point to extensive and reciprocal regulatory interactions between lncRNA and the translation machinery.
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